Leukemia/Lymphoma Archives - Sanford Burnham Prebys

Dr. Tautz develops novel drugs targeting protein tyrosine phosphatases that are implicated in cancer, thrombosis, and Alzheimer’s disease.

Dr. Tautz earned his PhD in Organic Chemistry and Biochemistry from the University of Karlsruhe (Germany) with Dr. Janos Retey in 2002. He continued his research at the Burnham Institute with Dr. Tomas Mustelin, first as a postdoc and later as a staff scientist. In 2009 Dr. Tautz joined the faculty of the Sanford Burnham Prebys Medical Discovery Institute.

Education

2002: PhD, University of Karlsruhe, Germany, Chemistry, Biochemistry
1997: MS, University of Karlsruhe, Germany, Chemistry

Funding Awards and Collaborative Grants

American Heart Association Innovative Research Grant

Honors and Recognition

2014: Semifinalist, Stadtman Investigator Search, National Institutes of Health
2008/2006 : Society for Biomolecular Sciences Travel Awards
2006: American Chemical Society Travel Award
2006: William and Lillian Fishman Award for Exceptional Postdoctoral Research
2002: PhD in Chemistry magna cum laude, University of Karlsruhe, Germany

Related Disease
Alzheimer’s Disease, Cancer, Cardiovascular Diseases, Inflammatory/Autoimmune Disease, Leukemia/Lymphoma, Neurodegenerative and Neuromuscular Diseases

Many human diseases stem from abnormalities in the activities of protein kinases and protein phosphatases. While efficacious therapeutics targeting protein kinases have been successfully used in the clinic (e.g., Gleevec), effective strategies to target specific protein phosphatases are still elusive. Dr. Tautz’ laboratory works on novel, more effective approaches to target these important enzymes. He focuses on protein tyrosine phosphatases implicated in cancer, thrombosis, autoimmunity, and Alzheimer’s disease.

Lutz Tautz’s Research Report

1. Discovery of a Novel Drug Target in Arterial Thrombosis

Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. In collaboration with researchers at the University of Liege in Belgium (Drs. Souad Rahmouni and Cecile Oury), we recently identified DUSP3 (also known as VHR) as a major regulator in platelet signaling and thrombosis. Intriguingly, bleeding was not affected by DUSP3 deficiency in mice, suggesting that DUSP3 plays a key role in arterial thrombosis, but is dispensable for primary hemostasis. We develop a specific small-molecule inhibitor of DUSP3 that effectively inhibited platelet aggregation in human platelets, thereby phenocopying the effect of DUSP3 deficiency in murine platelets. We are now poised to optimize this compound for in vivo studies in order to provide proof-of-concept for a novel and potentially safer antiplatelet strategy based on DUSP3.

Publications:

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis Musumeci L et al. Circulation. 2015 Feb 17;131(7):656-68.
Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy. Tautz L et al. Bioorg Med Chem. 2015 Jun 15;23(12):2786-97.

2. Discovery of a Novel Mechanism in T Cell Activation

PTPs are crucial for maintaining the homeostasis of the immune system, including the regulation of antigen receptor-mediated lymphocyte activation and cytokine-induced differentiation. The lymphoid tyrosine phosphatase (LYP, PTPN22) is a critical negative regulator of T cell antigen receptor signaling. A single-nucleotide polymorphism (SNP) in PTPN22 was shown to correlate with the incidence of various autoimmune diseases, including type 1 diabetes and rheumatoid arthritis. First, we helped to demonstrate that the disease-associated allele is a gain-of-function mutant, i.e. a better inhibitor of T cell receptor activation. Then, we developed a specific chemical probe of LYP which we utilized to identify the associated mechanism that leads to increased LYP activity. In contrast to what was known from work in mice, we showed that in human cells LYP needs to dissociate from CSK in order to inhibit T cell activation. We also showed that our LYP inhibitor acts by stabilizing a unique inactive conformation of LYP.

Publications:

Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Vang T et al. Nat Genet. 2005 Dec;37(12):1317-9.
In Silico Screening for PTPN22 Inhibitors: Active Hits From an Inactive Phosphatase Conformation. Wu S et al. ChemMedChem. 2009 Mar;4(3):440-4.
Inhibition of Lymphoid Tyrosine Phosphatase by Benzofuran Salicylic Acids. Vang T et al. J Med Chem. 2011 Jan 27;54(2):562-71.
LYP inhibits T cell activation when dissociated from CSK. Vang T et al. Nat Chem Biol. 2012 Mar 18;8(5):437-46.

3. Chemical Probe Development for Cancer Research

We have been working on chemical probes for cancer targets for several years (e.g., VHR, HePTP). Currently, we focus on the role of SHP2 in leukemia and breast cancer. PTPN11, the gene encoding SHP2, has been widely recognized as an oncogene. Germline mutations in PTPN11 were first observed in ~50% of cases of Noonan syndrome, an autosomal dominant developmental disorder with increased risk of malignancy. Numerous somatic gain-of-function mutations in PTPN11 have been identified in various leukemias. Hyperactivated SHP2 was also found in several types of solid tumors, including breast cancer. Previously reported SHP2 inhibitors lack efficacy in cancer cells and/or selectivity over related homologs. Novel SHP2 antagonists are needed for proof-of-principle studies that support a therapeutic approach based on SHP2. We have identified novel SHP2 lead compounds with significantly improved efficacy and selectivity. Currently, we optimize these compounds to make them suitable for in vivo studies.

Publications:

Multidentate Small-Molecule Inhibitors of Vaccinia H1-Related (VHR) Phosphatase Decrease Proliferation of Cervix Cancer Cells. Wu S et al. J Med Chem. 2009 Nov 12;52(21):6716-23.
Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids. Bobkova EV et al. ACS Med Chem Lett. 2011 Feb;2(2):113-118.
A Specific Inhibitor of Hematopoietic Protein Tyrosine Phosphatase Augments ERK1/2 and p38 Activation in vivo. Sergienko E et al. ACS Chem Biol. 2012 Feb 17; 7(2): 367–377.
Protein tyrosine phosphatases: structure, function, and implication in human disease. Tautz L et al. Methods Mol Biol. 2013;1053:179-221.

4. Targeting STEP in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by a progressive loss of cognitive function. The FDA has approved four drugs to treat the cognitive deficits in AD (donepezil, galantamine, rivastigmine, and memantine). However, none of these drugs halt disease progression. Our collaborator Dr. Paul Lombroso (Yale) identified the STriatal-Enriched Phosphatase (STEP) as a novel therapeutic target involved in the initial synaptic dysfunction that occurs prior to loss of neurons. His work suggests that inhibition of STEP could provide a disease-modifying strategy and early treatment option for AD. We recently received funding from the Alzheimer’s Association to develop a high-throughput assay to screen large chemical libraries for compounds that inhibit STEP function in neuronal cells. Once such compounds are identified, we will test their potential to reverse the biochemical and cognitive defects in AD animal models.

Publications:

Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer’s Disease. Xu J et al. PLoS Biol. 2014 Aug 5;12(8):e1001923.

Select Publications

Showing 3 of 3

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy.

Tautz L, Senis YA, Oury C, Rahmouni S

Bioorg Med Chem 2015 Jun 15 ;23(12):2786-97

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis.

Musumeci L, Kuijpers MJ, Gilio K, Hego A, Théâtre E, Maurissen L, Vandereyken M, Diogo CV, Lecut C, Guilmain W, Bobkova EV, Eble JA, Dahl R, Drion P, Rascon J, Mostofi Y, Yuan H, Sergienko E, Chung TD, Thiry M, Senis Y, Moutschen M, Mustelin T, Lancellotti P, Heemskerk JW, Tautz L, Oury C, Rahmouni S

Circulation 2015 Feb 17 ;131(7):656-68

Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer’s disease.

Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, Kanyo J, Zhang Y, Seyb K, Ononenyi C, Foscue E, Anderson GM, Gresack J, Cuny GD, Glicksman MA, Greengard P, Lam TT, Tautz L, Nairn AC, Ellman JA, Lombroso PJ

PLoS Biol 2014 Aug ;12(8):e1001923

View All Publications

A career history of fundamental discovery and translational research in immunology has guided Dr. Ware to identify new drug targets and develop novel therapeutics. Dr. Ware’s career in immunology and virology began in 1982 when he became a Professor at the University of California, Riverside’s Division of Biomedical Sciences. In 1996, he joined the La Jolla Institute for Immunology in San Diego as Head of the Division of Molecular Immunology. Professor Ware joined Sanford Burnham Prebys Medical Discovery Institute in 2010, serving as the Director of the Infectious and Inflammatory Disease Center and Adjunct Professor of Biology at the University of California at San Diego. He is currently the Director of the Laboratory of Molecular Immunology, which focuses on discovering and designing immunotherapeutics.

As an educator, he taught medical students immunology and virology. He trained over 60 postdoctoral fellows and graduate students who chose careers in research in academic and pharmaceutical science, patent law, or teaching.

Dr. Ware advises scientific panels and review boards for the National Institutes of Health and serves on the scientific advisor boards for the Allen Institute for Immunology and the Arthritis National Research Foundation. Scientific advisor with several biotechnology and pharmaceutical companies on immunotherapy for cancer and autoimmune diseases using innovative approaches to target discovery and drug development.

Dr. Ware’s research program is dedicated to unraveling the intricate intercellular communication pathways that govern immune responses. His work, which centers on cytokines in the Tumor Necrosis Factor (TNF) Superfamily, particularly those that regulate cell survival and death in response to viral pathogens, spans the domains of cancer,autoimmune and infectious diseases.

At Sanford Burnham Prebys, Dr. Ware is pivotal in promoting the translation of the faculty’s scientific discoveries. His efforts have led to the Institute’s reputation as a productive and preferred partner in collaborations with Pharma, including multi-year research and drug development projects with Eli Lilly and Avalo Therapeutics. His success translating fundamental knowledge into rational drug design has led to three novel therapeutics targeting inflammatory pathways, currently in clinical trials.

Education

1981-1982: T cell Immunology, Dana-Farber Cancer Institute of Harvard Medical School in Boston, MA. Tim Springer and Jack Strominger, advisors.
1979-1981: Biochemistry of Complement, University of Texas Health Science Center, San Antonio, TX. W Kolb, advisor
1974-1979: PhD in Molecular Biology and Biochemistry from the University of California, Irvine; Gale Granger, PhD mentor.

Honors and Recognition

Distinguished Fellow, American Association of Immunologists
Honorary Lifetime Membership Award International Cytokine and Interferon Society
Hans J. Muller-Eberhardt Memorial Lecture
Biotech All Star, San Diego Padres Award
“Pillars of Immunology” discovery of the Lymphotoxin-b Receptor, published in Science
Outstanding Alumnus, Ayala School of Biological Sciences, University of California, Irvine
National MERIT Award R37 (10 years), National Institute of Allergy and Infectious Disease, NIH
National Research Service Award, NIH Postdoctoral Fellowship

Related Disease
Arthritis, Breast Cancer, Cancer, Crohn’s Disease (Colitis), Infectious Diseases, Inflammatory Bowel Disease, Inflammatory/Autoimmune Disease, Inherited Disorders, Leukemia/Lymphoma, Myeloma, Pathogen Invasion, Psoriasis, Systemic Lupus Erythematosus, Type 1 Diabetes

Research in the Laboratory of Molecular Immunology is directed at defining the intercellular communication pathways controlling immune responses. Our work is focused on the Tumor Necrosis Factor (TNF)-related cytokines in regulating decisions of cell survival and death, especially in responses to viral pathogens. Translational research is redirecting the communication networks of TNF superfamily to alter the course of autoimmune and infectious disease and cancer.

Carl Ware’s Research Report

Discovery of the TNF-LIGHT-LTαβ Network

The molecular elements of this cellular communication network were revealed with our discovery of Lymphotoxin-β and its formation of the trimeric heterocomplex with LTαβ¹ and its signaling receptor, Lymphotoxin-β Receptor². The LTβR revealed a new inter-cellular communication pathway that provides a key mechanism underlying the development and homeostasis of lymphoid organs. A second ligand we discovered, LIGHT (TNFSF14), is a novel ligand for the herpesvirus entry mediator (HVEM; TNFRSF14), and surprisingly, the LTβR³ heralding the concept that TNF, LTαβ, and LIGHT form an integrated signaling network thru distinct receptors controlling inflammation and host defense.⁴

LTβR Signaling in Host Defense and Immune Evasion

Our investigations into the mechanisms of virus evasion of the immune system revealed an essential role of the LTβR pathway in regulating the type 1 interferon response to cytomegalovirus⁵ and now recognized as a major defense against other pathogens. LTβR signals differentiate macrophages and stromal cells into IFN-producing cells. LTβR transcriptomics and proteomics datasets we generated revealed a novel constellation of anti-viral host defense mechanisms⁶. Importantly the role of the LTβR pathway to alter tissue microenvironments by differentiation of specialized stromal cells has implications for promoting effective immune responses to cancer.

Discovery of the HVEM-BTLA Immune Checkpoint

The LTBR-HVEM-BTLA Network in the TNF Superfamilies. Arrows indicate ligand-receptor binding (black), inhibitors (red arrow) and bidirectional signaling (dual arrowheads); HSV, herpes simplex virus; CMV, human cytomegalovirus. BTLA and CD160 are Ig Superfamily proteins. BTLA is an inhibitory checkpoint receptor; DcR3, decoy receptor 3 inhibits LIGHT binding to HVEM and LTBR.

The discovery that HVEM is a coreceptor for the immune checkpoint, B and T lymphocyte attenuator (BTLA), an Ig superfamily member, established a new paradigm in TNF Receptor signaling pathways ⁷. Additional investigations revealed the importance of the HVEM-BTLA system in limiting immune responses, including T cell help for B cell clonal expansion, antibody maturation, and secretion⁸. HVEM-BTLA also regulates control of the intestinal microbiome, limiting invasion of pathogenic bacteria and enhancing Treg cell homeostasis ⁹. The diverse roles of this pathway are seen in the loss of BTLA signaling from mutations in HVEM frequently present in B cell lymphomas¹⁰. Additional layers of immune regulators, CD160 and DcR3, control the LIGHT-HVEM-BTLA pathways, revealing this network as a key mechanism controlling immune homeostasis.

Appreciating the fundamental features of the TNF-LIGHT-LTab Network in effector and homeostasis mechanisms presents a target-rich resource for therapeutic intervention in autoimmunity, infection, and cancer^{11, 12}.

Translational research and Immunotherapy

2021-current: Lead Scientific Advisor, Avalo Therapeutics
A neutralizing, fully human mAb (quisovalimab) to the proinflammatory cytokine LIGHT (TNFSF14) completed Phase I with an excellent safety profile and a Phase II trial establishing efficacy in COVID-19 pneumonia (NCT0441205)¹³. We identified elevated serum levels of LIGHT in hospitalized patients with COVID19¹⁴ spurring a randomized, double-blind, multicenter, proof-of-concept trial with adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS¹⁵. The results established efficacy with a significant proportion of patients remaining alive and free of respiratory failure through day 28 after receiving quisovalimab, most pronounced in patients >60 years of age (76.5% vs. 47.1%, respectively; P = 0.042). These results and animal models validated LIGHT as a target for non-COVID inflammatory conditions, clinical trials ongoing in asthma (NCT05288504)¹².
2021-current: Principal Investigator, Avalo Therapeutics – Sanford Burnham Prebys collaboration
Bioengineered a first-in-class checkpoint agonist targeting BTLA immune checkpoint¹⁶ in preclinical development
2019-current: Director and Principal Investigator, Fair Journey Biologics – Sanford Burnham Prebys collaboration
Immunotherapy for TNBC and PANC, in preclinical development
2015-2022: Director and Lead Principal Investigator, LILLY-Sanford Burnham Prebys Collaboration in Autoimmunity
Collaborative research partnership with Eli Lilly involved target discovery and therapeutic development directed at immune regulators for autoimmune diseases. The collaboration produced three novel biologics currently in Phase I/2 trials (NCT03933943). The collaboration included a target discovery platform for T cell effector memory and NK cell immunomodulators.
2015-2020: Lead Principal Investigator, Sanford Burnham Prebys – Capella Biosciences collaboration
Created a fully human mAb specific for membrane LIGHT (CBS001); phase I initiated (NCT05323110).
2016-2020: Lead Scientific Investigator, Boehringer Ingelheim – Sanford Burnham Prebys Collaboration
Target discovery collaboration in inflammatory and fibrotic diseases⁶
2012-2014: Pfizer Innovation Center, Principal Investigator Bioengineering TNFR Superfamily in Autoimmune disease

1. Browning, J.L. et al. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 72,847-856 (1993).
2. Crowe, P.D. et al. A lymphotoxin-beta-specific receptor. Science 264,707-710 (1994).
3. Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8,21-30 (1998).
4. Ward-Kavanagh, L.K., Lin, W.W., Sedy, J.R. & Ware, C.F. The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44,1005-1019 (2016).
5. Schneider, K. et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 3,67-76 (2008).
6. Virgen-Slane, R. et al. Cutting Edge: The RNA-Binding Protein Ewing Sarcoma Is a Novel Modulator of Lymphotoxin beta Receptor Signaling. J Immunol 204,1085-1090 (2020).
7. Sedy, J.R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6,90-98 (2005).
8. Mintz, M.A. et al. The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis. Immunity 51,310-323 e317 (2019).
9. Stienne, C. et al. Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa. Cell reports 38,110553 (2022).
10. Sedy, J.R. & Ramezani-Rad, P. HVEM network signaling in cancer. Adv Cancer Res 142,145-186 (2019).
11. Croft, M., Benedict, C.A. & Ware, C.F. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12,147-168 (2013).
12. Ware, C.F., Croft, M. & Neil, G.A. Realigning the LIGHT signaling network to control dysregulated inflammation. J Exp Med 219 (2022).
13. Zhang, M., Perrin, L. & Pardo, P. A Randomized Phase 1 Study to Assess the Safety and Pharmacokinetics of the Subcutaneously Injected Anti-LIGHT Antibody, SAR252067. Clin Pharmacol Drug Dev 6,292-301 (2017).
14. Perlin, D.S. et al. Levels of the TNF-Related Cytokine LIGHT Increase in Hospitalized COVID-19 Patients with Cytokine Release Syndrome and ARDS. mSphere 5 (2020).
15. Perlin, D.S. et al. Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome. J Clin Invest 132 (2022).
16. Sedy, J.R. et al. A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292,21060-21070 (2017).

Select Publications

Showing 3 of 3

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

Croft M, Salek-Ardakani S, Ware CF

Nat Rev Drug Discov 2024 Dec ;23(12):939-961

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.

Cheung TC, Atwell S, Bafetti L, Cuenca PD, Froning K, Hendle J, Hickey M, Ho C, Huang J, Lieu R, Lim S, Lippner D, Obungu V, Ward-Kavanagh L, Weichert K, Ware CF, Vendel AC

Structure 2023 Aug 3 ;31(8):958-967.e3

Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome.

Perlin DS, Neil GA, Anderson C, Zafir-Lavie I, Raines S, Ware CF, Wilkins HJ

J Clin Invest 2022 Feb 1 ;132(3):

View All Publications

Kristiina Vuori earned her MD and PhD at University of Oulu, Finland. After completion of internship and residency, she received postdoctoral training at the Institute and was appointed to faculty in 1996. Dr. Vuori was selected as a PEW Scholar in the Biomedical Sciences in 1997. She has been co-Director of the Conrad Prebys Center for Chemical Genomics, housed at Sanford Burnham Prebys, since its inception in 2005. She was appointed Deputy Director of the Institute’s NCI-Designated Cancer Center in 2003, and Director of the Cancer Center in 2006. In 2008, she was appointed Executive Vice President for Scientific Affairs at Sanford Burnham Prebys. She was President of the Institute from 2010 to 2022.

Related Disease
Brain Cancer, Breast Cancer, Cancer, Leukemia/Lymphoma, Lung Cancer, Ovarian Cancer, Prostate Cancer

Dr. Vuori’s research is aimed at unraveling the cell mechanisms of the most life-threatening aspect of cancer, which is cancer metastasis. Metastasis is responsible for nearly all deaths in cancer patients, and understanding of the mechanisms that turn a cancer from a locally growing tumor into highly metastatic cancer cells will provide clues how to prevent this step in cancer progression. All cells in our body stick to one another and to the packaging material, or extracellular matrix, around them. This adhesion is essential for cell survival; if cells become detached from their microenvironment, they will die through a process known as apoptosis. This phenomenon, which is called adhesion dependency of survival, is one of the safeguards that maintain the integrity and normal function of tissues, and prevent cells from becoming cancerous. Normal cells cannot detach from their tissue and establish themselves somewhere else, because they will die on the way. Yet cancer cells somehow get around this requirement; they trespass aggressively into other tissues and metastasize to distant sites in the body without dying. Dr. Vuori’s work is aimed at identifying the molecular mechanisms that in normal cells makes them adhesion-dependent; false action of the very same mechanisms is likely to be the key step in allowing cancer cells to metastasize.

Select Publications

Showing 3 of 3

Sceptrin, a marine natural compound, inhibits cell motility in a variety of cancer cell lines.

Cipres A, O’Malley DP, Li K, Finlay D, Baran PS, Vuori K

ACS Chem Biol 2010 Feb 19 ;5(2):195-202

Critical role for caspase-8 in epidermal growth factor signaling.

Finlay D, Howes A, Vuori K

Cancer Res 2009 Jun 15 ;69(12):5023-9

Cell biology. Two lipids that give direction.

Côté JF, Vuori K

Science 2009 Apr 17 ;324(5925):346-7

View All Publications

Xueqin (Sherine) Sun seeks to better understand the genetic and epigenetic underpinnings of cancers, using genome editing technologies, animal and patient-derived models, and other tools to develop more effective cancer therapies.

“My lab is interested in studying how DNA or the machinery that interprets it leads to the transformation of normal cells into cancerous cells and concurrently, their specific vulnerabilities. Identifying these intrinsic vulnerabilities and targeting them properly is profoundly important to developing effective cancer therapies.”

Another aspect of Sun’s work is understanding how cancer cells and tumors change their circumstances and environment to improve survival, including hiding from or repressing the immune system.

“Changes to DNA itself and the way how DNA is interpreted by cells can transform normal cells into cancer cells. And transformed cells propagate by enhancing the misinterpreted DNA information, which in turn becomes the Achilles’ heel of cancer cells. Our goal is to find out how DNA information is misinterpreted in different ways and how to correct it to halt cancer.”

At Sanford Burnham Prebys, Sun and colleagues will employ a host of leading-edge tools and approaches, including functional genomics, artificial intelligence, structural biology, large-scale drug screening, and advanced imaging/spatial technologies.

Sun conducted her postdoctoral fellowship at Cold Spring Harbor Laboratory under the guidance of Alea Mills, PhD, a professor at the National Cancer Institute-designated cancer center at Cold Spring Harbor.

She received her PhD from Wuhan University in China.

Related Disease
Aging-Related Diseases, Brain Cancer, Cancer, Childhood Diseases, Immune Disorders, Inflammatory/Autoimmune Disease, Leukemia/Lymphoma

Phenomena or Processes
Adapter Proteins, Adult/Multipotent Stem Cells, Aging, Angiogenesis, Apoptosis and Cell Death, Bcl-2 Family, Cancer Biology, Cancer Epigenetics, Cell Adhesion and Migration, Cell Biology, Cell Cycle Progression, Cell Differentiation, Cell Motility, Cell Proliferation, Cell Signaling, Cell Surface Receptors, Cellular Senescence, Chromosome Dynamics, Combinatorial Therapies, Cytokines, Development and Differentiation, Disease Therapies, DNA Damage Checkpoint Function, Embryonic/Pluripotent Stem Cells, Epigenetics, Gene Regulation, Genomic Instability, Growth Factors, Hematopoiesis, Host Defense, Host-Pathogen Interactions, Inflammation, Innate Immunity, Kinase Inhibitors, Metastasis, Neurogenesis, Oncogenes, Phosphorylation, Posttranslational Modification, Receptor Tyrosine Kinases, Serine/Threonine Kinases, Signal Transduction, TNF-Family, Transcription Factors, Transcriptional Regulation, Tumor Microenvironment, Tumorigenesis, Tyrosine Kinases, Ubiquitin, Ubiquitin Protease System and Ubiquitin-like Proteins

Anatomical Systems and Sites
Brain, General Cell Biology, Hematopoietic System, Immune System and Inflammation, Nervous System

Research Models
Bacteria, Cultured Cell Lines, Human Adult/Somatic Stem Cells, Human Cell Lines, Mouse, Mouse Cell Lines, Mouse Embryonic Stem Cells, Mouse Somatic Stem Cells, Primary Cells, Primary Human Cells

Techniques and Technologies
3D Image Analysis, 3D Reconstructions, Biochemistry, Bioinformatics, Cell Biology, Cellular and Molecular Imaging, Chemical Biology, Computational Biology, Confocal Microscopy, Correlative Light and Electron Microscopy, Drug Delivery, Drug Discovery, Drug Efficacy, Electron Microscopy, Fluorescence Microscopy, Fragment-Based Drug Design, Gene Expression, Gene Knockout (Complete and Conditional), Gene Silencing, Genetics, Genomics, High Content Imaging, High-Throughput/Robotic Screening, In vivo Modeling, Live Cell Imaging, Live Imaging, Mass Spectrometry, Microscopy and Imaging, Molecular Biology, Molecular Genetics, Nucleic Acid Synthesis, Protein-Protein Interactions, Protein-Small Molecule Interactions, Proteomics, Rational Drug Design, RNA Interference (RNAi), Scanning Cytometry, Small Molecule Compounds, Transgenic Organisms, Transplantation

We seek to understand why cancer occurs and what is the Achille’s heel of cancer, and to develop effective therapeutic interventions.

The successful treatment of any disease requires a good understanding of the mechanisms at work. Cancer is fundamentally caused by aberrant gene expression, which reflects the misinterpretation of DNA information at both genetic and epigenetic levels. We are interested in uncovering DNA-related alterations that drive cancer-favored transcriptional programs, identifying cancer-specific vulnerabilities, and developing effective therapeutic interventions for cancer treatment.

Xueqin Sun’s Research Report

Precise gene expression (the interpretation of DNA) is essential for almost all biological processes, and understanding gene regulation is one of the most pivotal frontiers in biological research under both health and disease circumstances. Gene expression is mainly regulated at genetic (with changes of DNA sequence) and epigenetic (without changing DNA sequence) levels. And gene dysregulation can lead to various health conditions and diseases, including developmental disorders, aging, and cancer. The overarching goal of Sun Lab is to uncover driving genetic and epigenetic alterations involved in cancer, to understand how developmental pathways and aging process impact cancer progression, and to identify mechanisms of action for developing more effective therapeutic strategies.

We are an interdisciplinary lab particularly focused on the following research directions:

The EP400 chromatin remodeling complex
The EP400 complex is an evolutionarily conserved SWR1-class ATP-dependent chromatin remodeling complex encompassing ~17 components, with a total molecular mass of ~1.5 mega-dalton. The EP400 complex plays critical roles in diverse cellular processes, including chromosome stability, transcription, DNA recombination, DNA damage repair, embryonic stem cell renewal/development, and oncogenesis. The EP400 complex can incorporate histone variants, such as H2AZ and H3.3, into the genome to regulate gene expression. Our recent work discovers BRD8—one of the core subunits of the EP400 complex—as a unique vulnerability of p53 wildtype glioblastoma (GBM), the most prevalent and devastating type of brain cancer. BRD8-driven EP400 complex highjacks H2AZ at p53 target loci to block p53-mediated transactivation and tumor suppression (Nature, 2023). The bromodomain of BRD8 plays the key role in this process. Bromodomain is a druggable domain as evidenced by a number of successful small molecules targeting diverse bromodomains encoded by the human genome across multiple cancer types. Furthermore, findings from others and us suggest that the EP400 complex is involved in different cancers. Thus, we seek to unravel the roles of the EP400 complex in health and disease, and to better understand how to target the EP400 complex for developing effective therapeutic interventions.
The NuRD chromatin remodeling complex
The NuRD complex is also a highly conserved class of ~ 1 MDa multi-subunit chromatin remodeling complexes that consume energy derived from ATP hydrolysis to remodel the configuration of chromatin to control gene transcription programs, with a primary role in gene silencing. Chromatin remodeling is vital for efficiently framing the cellular response to both intrinsic and extrinsic signals and has enormous implications for determining cellular states. NuRD complex is unique in combining ATP-dependent chromatin remodeling, protein deacetylase activity, and recognition of methylated DNA and histone modifications, and has multifarious roles in chromatin organization, transcription regulation, and genome maintenance; thereby, largely impacts health and disease. The NuRD complex has been in the central stage of brain development studies, and is significantly related to brain disorders/diseases. Interestingly, NuRD complex re-assembles by exchanging the chromatin remodeling subunits CHD3/4/5 to achieve specific regulation of an array of genes required for generating distinct cell types in a highly organized manner, especially over brain development. Amongst the genes encoding NuRD complex components, CHD5 is located in human chromosome 1 short arm (1p36), a region that is frequently hemizygously deleted in diverse cancers. Besides genetic deletion, CHD5 is also often silenced in cancer cells due to epigenetic mechanisms, such as promoter hypermethylation, aberrant expression of other chromatin regulators, and microRNAs-mediated translational repression and/or mRNA instability. Our current work seeks to determine whether and how CHD5-driven NuRD complex is involved in tumorigenesis (In preparation, 2024). We will further understand how NuRD complex is involved in both development and tumorigenesis, and identify mechanism of action to develop rational therapeutic strategies.
Novel genetic and epigenetic underpinnings in GBM
GBM is notorious for being a highly complex and plastic cancer type. However, at the genetic level, GBM harbors a relatively low genetic alteration burden compared to the majority of other cancers from pan-cancer profiling studies. This indicates the largely undocumented epigenetic mechanisms that interplay with genetic alterations and co-reprogram transcriptional networks essential for GBM development. Epigenetic changes are usually reversible by nature, as evidenced by numerous successes in targeting epigenetic regulators using small chemical compounds. As actionable therapeutic targets for GBM have been scarce, we are keen to uncover novel epigenetic pathways underlying gliomagenesis under different genetic backgrounds, which will potentially provide promising therapeutic opportunities for GBM treatment.
Novel GBM mouse models
Despite decades of effort, our knowledge about GBM biology is still very limited. GBM harbors a number of genetic alterations. However, among these recurrent genetic lesions, only several have been implicated in gliomagenesis, with most being undocumented. Moreover, the mechanisms by which these genetic alterations are involved in establishing GBM-favored epigenetic landscapes and transcription programs during GBM progression are still largely elusive. The lack of efficient approach to establish mouse models for investigating gene function in gliomagenesis and the limit of current mouse models to recapitulate clinical GBM features in brain is the prime reason that hinders GBM biological research. To this end, we have developed an engineered neural stem cells (NSCs)-based strategy to rapidly generate highly aggressive GBM with desired genetic lesions (genotypes) in mouse brain. Therefore, we will further optimize this strategy to establish a series of novel mouse models possessing recurrent combinations of genetic alterations (genotypes) in GBM, in order to systematically study whether and how these genetic lesions are involved in gliomagenesis and identify genotype-specific dependencies.
Crosstalk between GBM cells and tumor microenvironment
GBM exhibits highly diffuse and infiltrative nature, which contributes to therapeutic resistance and tumor relapse after surgical removal, resulting in dismal prognosis. A better understanding of gliomagenesis involving not only malignant cells themselves, but also the holistic bidirectional interactions of malignant cells with a variety of proximal and distal cells within the organism, is profound for developing novel effective therapies to improve GBM prognosis. Individual invasive GBM cells intermingle with normal brain cells and often cause relapse in brain areas essential for patient survival. Emerging evidence indicates that glioma cells highjack normal brain cells to thrive, and even transform them. However, how gliomagenesis reshapes ecological composition/landscape in host brain and how brain microenvironment affects gliomagenesis are still largely unclear. By using our novel highly invasive mouse models that recapitulate the multiforme diffuse topographies of GBM in brain, we seek to understand the interactions between GBM cells and brain microenvironment, and identify extrinsic pathways that are essential for GBM progression and migration.

Our lab is focused on both fundamental questions in cancer biology and translation of promising therapeutic strategies.

To achieve these, we work together with many fantastic collaborators to develop and leverage cutting-edge technologies, including but not limited to, high-throughput functional genomics (CRISPR/Cas9 screens, exon tiling scan, targeted mutagenesis, etc.), cell and molecular biology, genomics, epigenomics, proteomics, biochemistry, microscopy (2D/3D, time-lapse, two-photon, light sheet, etc.), automated large-scale drug synthesis/screening, structural biology, single cell and spatial multi-omics, artificial intelligence, and bioinformatics. We also establish novel patient-derived models and novel mouse models to facilitate our research programs. Our ultimate goals are to better understand fundamental genetic and epigenetic apparatuses involved in cancer-specific transcriptional networks, provide more effective therapeutic opportunities, and contribute to shifting the paradigms in cancer treatment and precision medicine.

Select Publications

Showing 1 of 1

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

Sun X, Klingbeil O, Lu B, Wu C, Ballon C, Ouyang M, Wu XS, Jin Y, Hwangbo Y, Huang YH, Somerville TDD, Chang K, Park J, Chung T, Lyons SK, Shi J, Vogel H, Schulder M, Vakoc CR, Mills AA

Nature 2023 Jan ;613(7942):195-202

View All Publications

Giovanni Paternostro earned his PhD in Biochemistry from the University of Oxford, England, in 1997. He has obtained his MD and Board Certification in Cardiology from the University of Rome, Italy. After postdoctoral training at the Imperial College School of Medicine, Hammersmith Hospital, London and at Sanford Burnham Prebys he was promoted to Research Investigator in 2001 and to Assistant Professor in 2003. In 2001 he was nominated member of the Whitaker Institute for Biomedical Engineering, UC San Diego. His research has been recognized by the 2002 Society for Geriatric Cardiology Basic Science Award and by the Ellison Medical Foundation New Scholar in Aging Award. Dr. Paternostro now holds adjunct faculty positions at Sanford Burnham Prebys Medical Discovery Institute and at the Department of Bioengineering, UC San Diego. His lab is located at Sanford Burnham Prebys.

Related Disease
Leukemia/Lymphoma, Ovarian Cancer

Our lab uses a systems biology approach to the study of complex diseases. Combined drug interventions are an increasingly common therapeutic approach to complex diseases, for example in cancer. Drugs are, however, usually developed individually and only later combined empirically in the clinic based on their known effects as single-therapy agents. We are interested in the problem of inducing selective cancer cell death. We have developed and validated search algorithms to discover optimal combinations of three or more drugs that would be infeasible to identify by fully combinatorial searches. In our procedure the optimization is not carried out in silico, but directly in an in vivo high-throughput system, where the response to therapeutic combinations is used as information to guide the system toward improved combinations using an iterative algorithm. System-wide molecular measurements (for example metabolomics and transcriptomics) and models can also be incorporated in these algorithms. It is useful to view the information processing by our experimental cellular systems as biological computations, since the algorithms we use are indeed often derived from algorithms that are implemented in silico in other scientific fields.

We also use the fruit fly (Drosophila) to study cardiac and metabolic alterations caused by aging and hypoxia, using high-throughput physiological measurements, NMR metabolomics and models of metabolism.

Our multi-disciplinary team is composed of biomedical and computational scientists, and we have close collaborations with physicists, engineers and bioengineers.

Select Publications

Showing 3 of 3

Integrating metabolomics and phenomics with systems models of cardiac hypoxia.

Feala JD, Coquin L, Paternostro G, McCulloch AD

Prog Biophys Mol Biol 2008 Jan-Apr ;96(1-3):209-25

Selective control of the apoptosis signaling network in heterogeneous cell populations.

Calzolari D, Paternostro G, Harrington PL Jr, Piermarocchi C, Duxbury PM

PLoS One 2007 Jun 20 ;2(6):e547

Flexibility in energy metabolism supports hypoxia tolerance in Drosophila flight muscle: metabolomic and computational systems analysis.

Feala JD, Coquin L, McCulloch AD, Paternostro G

Mol Syst Biol 2007 ;3():99

View All Publications

Dr. Ani Deshpande’s most recent position was as an Instructor with Dr. Scott Armstrong at the Memorial Sloan Kettering Cancer Center and the Children’s Hospital Boston/Harvard Medical School. He completed his PhD in Human Biology from the Ludwig Maximillians University in Munich. Dr. Deshpande’s research revolves around studying difficult-to-cure leukemias through the use of mouse models, genomic and epigenomic studies.

Funding Awards and Collaborative Grants

Ongoing Research Support R00 phase (number in process) Deshpande (PI) 10/0/14-present NIH/NCI – K99/R00 Howard Temin Pathway to Independence Award Role: PI (75% effort) Completed Research Support K99 CA154880 Deshpande (PI) 07/15/11-09/30/14 NIH/NCI – K99/R00 Howard Temin Pathway to Independence Award Role: Post-doctoral fellow/PI

Honors and Recognition

2014: American Society of Hematology Scholar Award (ASH Junior Faculty Scholar Award)
2013: Alex’s Lemonade Stand Foundation Travel Award for the FASEB Hematological Malignancies Meeting in Vermont, VA
2013: Abstract Achievement Award, American Society of Hematology Annual Meeting, New Orleans
2012: Abstract Achievement Award, American Society of Hematology Annual Meeting, Atlanta
2008: ASH Travel Award: 50th Annual Meeting, American Society of Hematology (ASH) San Diego
2008: The New York Stem Cell Foundation (NYSCF) Travel Grant, International Society of Stem Cell Research (ISSCR), Philadelphia
2007: The George Brecher New Investigator Award (postdoctoral) of the International Society of Experimental Hematology, Hamburg, Germany
2007: Doctoral prize of the German Society of Hematology and Oncology (Annual prize for the best doctoral thesis in hematology-oncology in Germany)
2007: The Doctoral Prize of the Helmholtz Centre, Munich for the Best Doctoral Thesis 2006, Munich, Germany
2007: Best Poster Award (2nd Prize): 36th Annual Scientific Meeting, International Society for Experimental Hematology (ISEH) Hamburg
2007: Travel Award: 36th Annual Scientific Meeting, International Society for Experimental Hematology (ISEH) Hamburg
2006: Summa Cum Laude Ludwigs Maximililans University, Munich, Germany
2005: ISEH Travel Grant: 34th Annual Scientific Meeting, International Society for Experimental Hematology (ISEH) Glasgow
2004: ISEH Travel Grant: 33rd Annual Scientific Meeting, International Society for Experimental Hematology (ISEH) New Orleans
2003: ASH Travel Award: 45th Annual Meeting, American Society of Hematology (ASH) San Diego

Related Disease
Cancer, Leukemia/Lymphoma

One of the core interests of the lab is to understand regulation of key developmental processes that are important for normal stem cells and are frequently misregulated in human cancer. We are currently investigating genetic and epigenetic abnormalities in Acute Myeloid Leukemia (AML) using mouse models, gene targeting and genome-scale approaches. Our overarching goal is to uncover therapeutic nodes of intervention in human leukemia.

Available Positions in the Deshpande Lab

We are seeking exceptional candidates with broad interests/expertise in cancer epigenetics and stem cell biology at the level of postdoctoral fellows, graduate students and undergraduates.

Graduate students
Applicants interested in graduate positions should send their applications to the Sanford Burnham Prebys Medical Discovery Institute Graduate School for Biomedical Sciences. The application period opens in the fall.
Undergraduate students
Please contact Dr. Deshpande via email adeshpande@SBPdiscovery.org .

Ani Deshpande’s Research Report

Normal and malignant stem cells: One of the core interests of the lab is to investigate the role of chromatin regulators in benign and malignant hematopoiesis. Several attributes of normal stem cells such as the ability to self-renew are co-opted or reactivated by cancer cells on their way to malignant transformation. We are interested in characterizing the molecular determinants of “stemness” using hematopoietic stem cells as a model and in identifying ways and means by which these stem-cell associated pathways are usurped for oncogenesis.

The leukemia epigenome: Abnormal epigenetic changes have emerged as important mediators of oncogenesis. Genomic investigations of human cancer have uncovered mutations in writers, erasers and readers of the histone code. The goal of our laboratory is to connect basic mechanisms of chromatin regulation to diseased states with a focus on Acute Myeloid Leukemia (AML). Ultimately, we are interested in the rational design of screens to develop therapeutics targeting dysregulated epigenetic mechanisms in AML.

Chromosomal translocations in cancer: Ever since the discovery of the Philadelphia chromosome in 1960, a number of different chromosomal translocations have been identified in human cancer that result in the formation of potent fusion oncogenes, abnormal activation of latent proto-oncogenes, or other oncogenic events. We are very interested in investigating the impact of chromosomal translocations on the development of human cancer. Moreover, we are also interested in understanding the propensity of certain genomic loci for recurrent involvement in oncogenic chromosomal translocation events in the context of human myeloid malignancies.

Select Publications

Showing 2 of 2

Chromatin modifications as therapeutic targets in MLL-rearranged leukemia.

Deshpande AJ, Bradner J, Armstrong SA

Trends Immunol 2012 Nov ;33(11):563-70

Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.

Deshpande AJ, Chen L, Fazio M, Sinha AU, Bernt KM, Banka D, Dias S, Chang J, Olhava EJ, Daigle SR, Richon VM, Pollock RM, Armstrong SA

Blood 2013 Mar 28 ;121(13):2533-41

View All Publications

Dr. Blaho began her research career focused on how bioactive lipids contribute to the innate immune response against bacterial infection, characterizing roles for eicosanoids in the generation and resolution of Lyme arthritis pathology. The wild diversity of lipid species led Dr. Blaho to Weill Cornell Medical College in New York City to pursue postdoctoral training in the field of sphingolipids, particularly sphingosine 1-phosphate (S1P), and its receptors. Advancing to Instructor at Weill Cornell and later, Research Assistant Professor at Sanford Burnham Prebys, Dr. Blaho continued her research in lipid chaperones and receptor signaling, with an emphasis on cell-type differential effects on hematopoiesis and immunity in response to cell stressors. In August of 2019, Dr. Blaho joined the faculty at the Institute as an Assistant Professor in the Immunity and Pathogenesis program.

Why do you do what you do?

The immune system has the power to protect us from invading pathogens and cancer or to initiate a “self-destruct” sequence that consumes us with inflammation and autoimmunity. It is fascinating to me that a simple ubiquitous fat molecule like S1P can control the birth and destiny of immune cells.

Education

2014-2016: Instructor, Weill Cornell Medicine, Pathology and Laboratory Medicine and Neuroscience
2009-2014: Post-doctoral training, Weill Cornell Medicine, Pathology and Laboratory Medicine
2007-2009: Post-doctoral training, University of Missouri, Columbia, Veterinary Pathobiology
2007: PhD, University of Missouri, Columbia, Molecular Microbiology and Immunology – BS

Funding Awards and Collaborative Grants

National Heart, Lung, and Blood Institute R01
American Heart Association Scientist Development Grant
2014-15: Leon Levy Neuroscience Foundation Grant
2015: Foundation LeDucq SphingoNet Young Investigator Grant
2009-12: National Cancer Institute Individual Ruth L. Kirschstein Post-doctoral Fellowship

Honors and Recognition

2017: British Journal of Pharmacology Lecture: FASEB Summer Research Conference on Lysophospholipids and Related Mediators – from bench to clinic.
2014: Leon Levy Foundation Neuroscience Fellow
2010: Keystone Scholarship, Bioactive Lipids: Biochemistry and Diseases
2008: Keystone Scholarship, Eicosanoids and Other Mediators of Chronic Inflammation
2007: Young Investigator Award in Inflammation, Eicosanoid Research Foundation
2004: National Academy of Sciences Christine Mirzayan Policy Fellow, Institute of Medicine Board on Health Sciences Policy

Related Disease
Biochemistry, Immune Disorders, Inflammatory/Autoimmune Disease, Leukemia/Lymphoma, Molecular Biology, Multiple Sclerosis

Phenomena or Processes
Adaptive Immunity, Apoptosis and Cell Death, Cell Signaling, G-Protein Coupled Receptors, Hematopoiesis, Inflammation, Innate Immunity

Anatomical Systems and Sites
Hematopoietic System, Immune System and Inflammation, Vasculature

Research Models
Human Adult/Somatic Stem Cells, Mouse, Mouse Somatic Stem Cells, Primary Cells

Techniques and Technologies
Cell Biology, Cellular and Molecular Imaging, Confocal Microscopy, Fluorescence Microscopy, Gene Expression, Lipid Bilayers, Mass Spectrometry

The lipid sphingosine 1 phosphate (S1P) is found in high levels in the blood and lymph and is primarily carried by the protein ApoM, found on HDL. S1P can affect the cardiovascular, nervous, and immune systems via interaction with cell surface-expressed receptors, S1P1-5. My work is determining how changing S1P carrier or receptor expression and signaling can affect cells of the immune system, particularly in the bone marrow, and how this alters their ability to respond to stress or infection.

Select Publications

Showing 3 of 3

HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.

Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL, Kono M, Proia RL, Steinman L, Han MH, Hla T

Nature 2015 Jul 16 ;523(7560):342-6

HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation.

Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, Dahlbäck B, Kono M, Proia RL, Smith JD, Hla T

Sci Signal 2015 Aug 11 ;8(389):ra79

An update on the biology of sphingosine 1-phosphate receptors.

Blaho VA, Hla T

J Lipid Res 2014 Aug ;55(8):1596-608

View All Publications

Dr. Adams most recently led the Epigenetics Unit at the Beatson Institute for Cancer Research and the University of Glasgow, Institute of Cancer Sciences, in Scotland. He has also held positions at Wistar Institute (University of Pennsylvania), Drexel University and Fox Chase Cancer Center in Philadelphia.

Peter D. Adams obtained his BA in biochemistry at the University of Oxford, England and his PhD at Imperial Cancer Research Fund (now CR-UK). He did postdoctoral work with Dr. William G. Kaelin, Jr. at Dana-Farber Cancer Institute. Peter D. Adams is co-Editor-in-Chief of the journal Aging Cell.

Education

1993: PhD, Signal Transduction, Imperial Cancer Research Fund (CRUK), London, UK (Dr. Peter Parker, advisor)
1989: B.A., Biochemistry, Oxford University, England

Honors and Recognition

2003-2008: Leukemia and Lymphoma Society Scholar
1999-2001: W.W. Smith Charitable Trust Fellowship
1999-2001: V Foundation Scholar
1995-1996: Cancer Research Foundation of America Fellowship
1993-1995: SERC/NATO Fellowship
1989: B.A. with Honors in Biochemistry, Oxford University, UK
1986: Awarded a Distinction in Oxford University Preliminary Examinations
1984-1989: 1984-1989: Exhibition holder for Academic Achievement at Oxford University, UK
1983: Lane Scholarship for Academic Achievement at King Henry VIII School, UK

Related Disease
Aging, Aging-Related Diseases, Colorectal Cancer, Leukemia/Lymphoma, Liver Cancer, Skin Cancer and Melanoma

Phenomena or Processes
Epigenetics

Dr. Adams’ lab investigates the impact of chromatin and epigenetics on cellular senescence, aging and cancer. In particular, the lab hypothesizes that age-associated changes in chromatin and epigenetic programming contribute to the dramatic age-associated increase in incidence of cancer. While age is the biggest single risk factor for most cancers, the reason for this is current poorly understood.

Dr. Adams’ research focus is driving epigenetics as a cross-cutting scientific theme and promoting access to single cell technologies at the Institute.

Peter D. Adams’ Research Report

We have mapped the epigenetic landscape of senescent cells, and are defining the causes and consequences of this altered landscape. Cellular senescence is an irreversible proliferation arrest and pro-inflammatory phenotype triggered in primary cells by activated oncogenes and other molecular stresses. As a profound change in cell phenotype, the initiation and maintenance of senescence depends on reprogramming of chromatin, the epigenome and gene expression. Cellular senescence is a potent tumor suppressor mechanism. However, the accumulation of senescent cells with age also causes tissue aging, by blocking cell and tissue renewal and driving chronic inflammation. Indeed, in contrast to its acute tumor suppressive effects, chronic accumulation of inflammatory senescent cells is tumor promoting. In collaboration with Dr. Shelley Berger, we have mapped the distribution of several critical epigenetic regulators in proliferating and senescent cells, including DNA methylation, several histone modifications, histone variants and nuclear lamins. These collaborative studies have yielded critical insights into gene regulation in senescent cells (Cruickshanks et al., 2013; Rai et al., 2014; Shah et al., 2013), and the tumor suppressive and pro-aging effects of senescent cells (Cruickshanks et al., 2013; Nelson et al., 2016).

Senescent cells harbour features of the cancer epigenome. Cruickshanks, H.A., McBryan, T., Nelson, D.M., Vanderkraats, N.D., Shah, P.P., van Tuyn, J., . . . Adams, P.D. Nat Cell Biol. 2013 Dec ;15(12):1495-506
Mapping H4K20me3 onto the chromatin landscape of senescent cells indicates a function in control of cell senescence and tumor suppression. Nelson, D.M., Jaber-Hijazi, F., Cole, J.J., Robertson, N.A., Pawlikowski, J.S., Norris, K.T., Criscione, S.W., Pchelintsev, N.A., Piscitello, D., Stong, N., Rai, T.S., McBryan, T., ……Adams, P.D. Genome Biol. 2016 Jul 25;17(1):158
HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Rai, T.S., Cole, J.J., Nelson, D.M., Dikovskaya, D., Faller, W.J., Vizioli, M.G., . . . Adams, P.D. Genes Dev. 2014 Dec 15;28(24):2712-25
Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Shah, P.P., Donahue, G., Otte, G.L., Capell, B.C., Nelson, D.M., Cao, K., . . . Adams*, P.D. Berger*, S.L. Genes Dev. 2013 Aug 15;27(16):1787-99. * Co-corresponding authors.

Landmark structure and functional studies on the HIRA histone chaperone complex and its role in senescence-mediated tumor suppression. In collaboration with Dr. Ronen Marmorstein in Philadelphia we have dissected the structure-function relationships between HIRA and its binding partners, UBN1, CABIN1 and ASF1a and substrate histone H3.3 (Zhang et al., 2005). This included a crystal structure of the HIRA/ASF1a interaction surface and more recently the UBN1/histone H3.3 interaction surface (Tang et al., 2006). We were the first to describe the distribution of the HIRA complex across the mammalian epigenome (Pchelintsev et al., 2013). In functional studies, we have demonstrated the role of this DNA replication independent histone chaperone complex in the control of chromatin in non-proliferating senescent cells (Rai et al., 2014). These studies have been facilitated by the mouse monoclonal and rabbit polyclonal antibodies that we have made to all subunits of the complex. More recently, we have generated the first conditional knock out mice of HIRA, UBN1 and CABIN1 and are using these to establish in vivo functions (Rai et al., 2014). Of particular note, we have revealed a function for HIRA in promoting healthy aging and the suppression of cancer (Rai et al., 2014).

Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Zhang, R., Poustovoitov, M.V., Ye, X., Santos, H.A., Chen, W., Daganzo, S.M., . . . Adams, P.D. Dev Cell. 2005 Jan ;8(1):19-30
Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly. Tang, Y., Poustovoitov, M.V., Zhao, K., Garfinkel, M., Canutescu, A., Dunbrack, R., . . . Adams*, P.D., Marmorstein*, R. (2006) Nat Struct Mol Biol. 2006 Oct ;13(10):921-9
Placing the HIRA histone chaperone complex in the chromatin landscape. Pchelintsev, N.A., McBryan, T., Rai, T.S., van Tuyn, J., Ray-Gallet, D., Almouzni, G., and Adams, P.D. (2013). Cell Rep. 2013 Apr 25;3(4):1012-9
HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Rai, T.S., Cole, J.J., Nelson, D.M., Dikovskaya, D., Faller, W.J., Vizioli, M.G., . . . Adams, P.D. (2014). Genes Dev. 2014 Dec 15;28(24):2712-25

We coined the term “chromostasis” to describe the presumptive homeostatic mechanisms that confer epigenetic stability over the lifecourse, and we were major contributors to the first demonstration of a DNA methylation clock in the mouse. Maintenance of cell phenotype and suppression of disease, including cancer, over the lifecourse depends on a high level of epigenetic stability. However, since chromatin is inherently dynamic (Rai et al., 2014), this steady state stability likely reflects a challenge for the cell. Therefore, presumptive “chromatin homeostasis” or “chromostasis” mechanisms are predicted to actively maintain an epigenetic steady state over the lifecourse, thereby suppressing age-associated disease (Rai et al., 2014). We have shown that histone chaperone HIRA is one such factor that contributes to epigenetic stability in non-proliferating cells (Ye et al., 2007). Recently, we reported the first DNA methylation clock in the mouse, and showed that diverse interventions – genetic, dietary and drug – that promote longevity of mice also suppress age-associated epigenetic changes and slow progression of this DNA methylation “clock”, i.e. enhance chromostasis (Cole et al., 2017; Wang et al., 2017).

HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Rai, T.S., Cole, J.J., Nelson, D.M., Dikovskaya, D., Faller, W.J., Vizioli, M.G., . . . Adams, P.D. (2014). Genes Dev. 2014 Dec 15;28(24):2712-25
Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Zhang, R., Poustovoitov, M.V., Ye, X., Santos, H.A., Chen, W., Daganzo, S.M., . . . Adams, P.D. Dev Cell. 2005 Jan ;8(1):19-30
Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Cole, J.J., Robertson, N.A., Rather, M.I., Thomson, J.P., McBryan, T. Sproul, D. Wang, T. Brock, C; Clark, W., Ideker, T. Meehan, R.R. Miller, R.A., Brown-Borg, H., Adams, P.D. Genome Biol. 2017 Mar 28;18(1):58
Epigenetic aging signatures in mice are slowed by dwarfism, calorie restriction and rapamycin treatment. Wang, T., Tsui, B., Kreisberg, J.F., Robertson, N.A., Gross, A.M., Carter, H., Brown-Borg, H., Adams, P.D, Ideker, T. Genome Biol. 2017 Mar 28;18(1):57

We have demonstrated a “tug of war” between tumor suppressive oncogene-induced senescence and oncogenic activated Wnt signaling in melanocytic neoplasia (Adams and Enders, 2008; Ye et al., 2007). The balance between these tumor suppressive and oncogenic activities determines the efficiency of senescence-mediated tumor suppression. For example, we showed that in oncogene-expressing melanocytes a low level of activated Wnt signaling promotes benign nevus formation (Pawlikowski et al., 2013). However, a high level of activated Wnt signaling, caused by germline sequence variants, promotes giant congenital nevi in the form of congenital melanocytic nevus (CMN) syndrome (Pawlikowski et al., 2015). In a mouse model that closely recapitulates the human genetics, we showed that activated Wnt signaling and an activated Ras oncogene (NRasQ61K) cooperate to drive CMN syndrome, and that this is suppressed by acute post-natal treatment with MEK inhibitors (Pawlikowski et al., 2015). Based on these studies, our collaborator Dr. Veronica Kinsler is preparing to test MEK inhibitors in babies afflicted by CMN syndrome.

Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Ye, X., Zerlanko, B., Kennedy, A., Banumathy, G., Zhang, R., and Adams, P.D. Mol Cell. 2007 Jul 20;27(2):183-196
Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling. Pawlikowski, J.S., Brock, C., Chen, S.C., Al-Olabi, L., Nixon, C., McGregor, F., . . . Adams, P.D. J Invest Dermatol. 2015 Aug;135(8):2093-2101
Wnt signaling potentiates nevogenesis. Pawlikowski, J.S., McBryan, T., van Tuyn, J., Drotar, M.E., Hewitt, R.N., Maier, A.B., . . . Adams, P.D. Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16009-14
Wnt signaling and senescence: A tug of war in early neoplasia? Adams, P.D., and Enders, G.H. Cancer Biol Ther. 2008 Nov;7(11):1706-11

We first characterized Cytoplasmic Chromatin Fragments (CCF) in senescent cells and in collaboration defined a role for CCF as drivers of inflammation via the cGAS/STING cytoplasmic DNA sensing anti- viral pathway. Cellular senescence is a potent tumor suppressor mechanism by virtue of proliferation arrest and the senescence associated secretory phenotype (SASP) which promotes clearance of pre-malignant cells by the immune system. However, the mechanism responsible for initiation of SASP has been unknown. In 2013, our lab first characterized and named CCF as fragments of chromatin expelled from the nucleus of senescent cells into the cytoplasm (Ivanov et al., 2013). Then, in 2015, in collaboration with Shelley Berger’s laboratory, we showed that formation of CCF depends on interaction of lamin B1 and autophagy adaptor LC3 in the nucleus, and that lamin B1 is a nuclear substrate of autophagy (Dou et al., 2015). Most recently, again with Shelley Berger’s lab, we have shown that CCF are sensed by the cytoplasmic DNA sensing anti-viral apparatus, cGAS and STING, and this leads to activation of NFkB and SASP in senescent cells (Dou et al., 2017). The role of CCF as triggers of SASP, via cGAS and STING, has been confirmed by several other labs. Most recently, we showed that formation of CCF is triggered by a retrograde mitochondria-to-nucleus signalling pathway that constututes a target for candidate anti-SASP healthy aging interventions (Vizioli et al., 2020).

Lysosome-dependent processing of histones in senescent cells. Ivanov, A., Pawlikowski, J., Manoharan, I., van Tuyn, J., Nelson, D. M., Rai, T. S., Shah, P. P., Drotar, M., Wu, H., Berger, S. L., and Adams, P.D. J. Cell Biol. 2013 July 1; 202 (1): 129–143
Autophagy mediates degradation of nuclear lamina. Dou, Z., Capell, BC., Drake, AM., Shah, PP., Dorsey, J., Simola, D., Donahue, G., Zhu, Z., Sammons, M., Rai, TS., Natale, C., Ridky, T., Goldman, R., Adams, P.D., Berger, SL. Nature. 2015 Oct 28; 527:105-109
Cytoplasmic chromatin triggers inflammation in senescence and cancer. *Corresponding authors. Dou, D., Ghosh, K., Vizioli, MG., Zhu, J., Sen, P., Wangensteen, KJ., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., Capell, BC., Xu, C., Xu, M., Kieckhaefer, JE., Jiang, T., Shoshkes-Carmel, M., Ahasan Al Tanim, KM., Barber, GN., Seykora, JT., Millar, SE., Kaestner, KH., Garcia, BA., Adams, P.D.*, Berger, SL*. Nature. 2017 Oct 4; 550:402-406
Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Vizioli, M.G., Liu, T., Miller, K.N., Robertson, N., Gilroy, K., Lagnado, A., Perez-Garcia, A., Kiourtis, C., Dasgupta, N., Lei, X., Kruger, P.J., Nixon, C., Clark, W., Jurk, D., Bird, T.G., Passos, J.F., Berger, S.L., Dou, Z., Adams, P.D. Genes and Dev. 2020 Jan 30; 34, 428-445

Select Publications

Showing 1 of 1

Cytoplasmic chromatin triggers inflammation in senescence and cancer.

Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, Simithy J, Lan Y, Lin Y, Zhou Z, Capell BC, Xu C, Xu M, Kieckhaefer JE, Jiang T, Shoshkes-Carmel M, Tanim KMAA, Barber GN, Seykora JT, Millar SE, Kaestner KH, Garcia BA, Adams PD, Berger SL

Nature 2017 Oct 19 ;550(7676):402-406

View All Publications

Biography

Education

Funding Awards and Collaborative Grants

Honors and Recognition

Research

Select Publications

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy.

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis.

Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer’s disease.

Biography

Education

Research

Select Publications

Novel HTS strategy identifies TRAIL-sensitizing compounds acting specifically through the caspase-8 apoptotic axis.

Sceptrin, a marine natural compound, inhibits cell motility in a variety of cancer cell lines.

Caspase-8 as a potential mediator of pro-tumorigenic signals.

Biography

Education

Honors and Recognition

Research

Select Publications

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.

Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome.

Biography

Research

Select Publications

Sceptrin, a marine natural compound, inhibits cell motility in a variety of cancer cell lines.

Critical role for caspase-8 in epidermal growth factor signaling.

Cell biology. Two lipids that give direction.

Biography

Research

Select Publications

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

Biography

Research

Select Publications

Integrating metabolomics and phenomics with systems models of cardiac hypoxia.

Selective control of the apoptosis signaling network in heterogeneous cell populations.

Flexibility in energy metabolism supports hypoxia tolerance in Drosophila flight muscle: metabolomic and computational systems analysis.

Biography

Funding Awards and Collaborative Grants

Honors and Recognition

Research

Select Publications

Chromatin modifications as therapeutic targets in MLL-rearranged leukemia.

Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.

Biography

Why do you do what you do?

Education

Funding Awards and Collaborative Grants

Honors and Recognition

Research

Select Publications

HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.

HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation.

An update on the biology of sphingosine 1-phosphate receptors.

Biography

Education

Honors and Recognition

Research

Select Publications

Cytoplasmic chromatin triggers inflammation in senescence and cancer.