Cancer Metabolism and Microenvironment Program Archives - Sanford Burnham Prebys

Tag: Cancer Metabolism and Microenvironment Program

Institute News

PERCEPTION proves a predictable NCI milestone

AuthorScott LaFee
Date

May 9, 2025

false-colored scanning electron micrograph of a breast tumor spheroid
A false-colored scanning electron micrograph of a breast tumor spheroid (cluster of cells). The spheroid has been treated with the anti-cancer drug doxorubicin, which is causing some cells to die (yellow). Healthy cells are colored pink and violet. Image courtesy of Khuloud T. Al-Jamal, David McCarthy and Izzat Suffian, Wellcome Collection.

PERCEPTION is the acronym for PERsonalized Single-Cell Expression-Based Planning for Treatments In Oncology, an artificial intelligence-based tool that, in findings first reported last year, was able to predict tumor response to targeted therapy using single-cell datasets.

The work, published in Nature Cancer, is the result of first study author Sanju Sinha, PhD, assistant professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, with senior authors Eytan Ruppin, MD, PhD, and Alejandro Schaffer, PhD, at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues.

Recently, the NCI’s Center for Cancer Research highlighted PERCEPTION in its 2024-2025 annual Milestones report.

The researchers said PERCEPTION not only helped predict which anti-cancer drugs are most effective for individual patients, but also tracked the evolution of drug resistance over the course of the disease and treatment — something never before achieved.

“A tumor is a complex and evolving beast. Using single-cell resolution can allow us to tackle both of these challenges, Sinha said when their findings were published. “PERCEPTION allows for the use of rich information within single-cell omics to understand the clonal architecture of the tumor and monitor the emergence of resistance.” (In biology, omics refers to the sum of constituents within a cell.)

“The ability to monitor the emergence of resistance is the most exciting part for me. It has the potential to allow us to adapt to the evolution of cancer cells and even modify our treatment strategy.”

PERCEPTION was previously named among the National Institutes of Health director’s highlights for 2024.

Institute News

Kelly Kersten awarded Melanoma Research Alliance grant to support research on melanoma immunotherapy

AuthorGreg Calhoun
Date

May 2, 2025

Kelly Kersten
Kelly Kersten, PhD, is an assistant professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. Credit: Sanford Burnham Prebys

The newly created Paul Walks – MRA Young Investigator Award in Memory of Chad Johnson is part of the alliance’s $9.3 million commitment to melanoma research funding in 2025.

Kelly Kersten, PhD, an assistant professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, was awarded a new type of grant from the Melanoma Research Alliance (MRA). The funding will support Kersten’s research on reactivating “exhausted” immune cells within melanoma tumors to restore their cancer-fighting ability and improve the effectiveness of melanoma immunotherapy.

“Inside tumors, immune cells often lose their strength to attack cancer,” said Kersten. “Our work is focused on understanding and reversing this exhaustion to make therapies more effective for more people.”

The MRA is the world’s leading nonprofit funder of melanoma research. The organization created the Paul Walks – MRA Young Investigator Award in Memory of Chad Johnson to provide support for the next generation of scientists driving innovation against melanoma.

“Our Young Investigator Awards fuel the creativity and drive of early-career scientists whose work can redefine the future of melanoma research.” said Joan Levy, PhD, MRA Chief Science Officer.

The new grant pays tribute to Chad Johnson, a beloved friend and surfer who died from his melanoma diagnosis at age 55. Funding for the award was made possible through “Paul Walks,” a community fundraiser organized by Chad’s lifelong friend, Paul Giobbi.

The Paul Walks – MRA Young Investigator Award in Memory of Chad Johnson is part of MRA’s $9.3 million commitment to fund melanoma research in 2025, supporting more than 30 researchers across the U.S., Europe and Australia. Melanoma remains the deadliest form of skin cancer, with more than 100,000 people expected to be diagnosed this year and one death every hour in the U.S. alone.

Institute News

Curebound awards two grants to Sanford Burnham Prebys scientists

AuthorGreg Calhoun
Date

February 12, 2025

split photo of Brooke Emerling and Michael Jackson
Brooke Emerling, PhD, is director of the Cancer Metabolism and Microenvironment Program. Michael Jackson, PhD, is senior vice president for Drug Discovery and Development in the Conrad Prebys Center for Chemical Genomics.

The San Diego-based philanthropic organization has awarded $43 million in cancer research to date

Curebound recently announced the awarding of 17 grants in December 2024 for a total of $8.25 million in funding to advance cancer research in 2024.

Two new grants will support cancer research conducted by scientists at Sanford Burnham Prebys. Since 2014, 32 Curebound grants have supported projects that included scientists at the institute.

A workaround for a tricky target

The TP53 gene contains the blueprint for constructing a protein called tumor protein p53. This protein is considered a tumor suppressor because it helps cells grow in a controlled manner.

When cell growth goes awry, however, the TP53 gene is a common culprit as the most frequently mutated gene in cancers. While this ubiquity has placed a bullseye on the mutated tumor protein p53 for aspiring drug developers, it has proven tricky to target directly.

Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program, and her collaborators have shown that the growth of cancer cells with a mutated TP53 gene is dependent on lipid enzymes called phosphatidylinositol-5-phosphate 4-kinases (PI5P4K). Emerling and her collaborators have identified compounds that break down these enzymes.

The researchers have demonstrated the ability of these compounds to target and eliminate cancer cells with a mutated TP53 gene without harming normal cells. Curebound will support the team’s ongoing efforts to work around the difficult-to-target tumor protein p53 by instead targeting PI5P4K.

Next, the group plans to optimize the compounds that break down PI5P4K to develop cancer drugs that are strong candidates for future clinical trials.

Curebound collaborators: Patrick Kearney, PhD, director of Medicinal Chemistry in the Conrad Prebys Center for Chemical Genomics, and Eric Wang, PhD, assistant professor in the Cancer Molecular Therapeutics Program.

Boosting the immune system against lung cancer

The immune system is one of the main defenses of the human body to fend off harmful pathogens and invasive cells such as cancer. Among all white blood cells, a particular cell type, called a T cell, can directly kill cancer cells and therefore plays an essential role in building anti-tumor immune responses.

Immunotherapies that boost the anti-cancer capabilities of T cells have revolutionized the way we treat cancer, especially in blood cancers such as leukemia, lymphoma and myeloma. More recently, immunotherapies are rapidly advancing to become mainstream treatments for solid cancers as well.

Currently, however, less than a third of patients with lung cancer benefit from immunotherapies. Pandurangan Vijayanand, MD, PhD, the William K. Bowes Distinguished Professor at the La Jolla Institute for Immunology, discovered that certain T cells called cytotoxic T lymphocytes have molecular features associated with a robust immune response against lung cancer tumors. His work has identified new targets for lung cancer immunotherapy.

Curebound will support Vijayanand’s collaboration with Michael Jackson, PhD, senior vice president for Drug Discovery and Development in the Conrad Prebys Center for Chemical Genomics, to use this research to identify agents to boost tumor immune responses.

The research team’s work has the potential to identify a new class of immunotherapy drugs for patients with lung cancer.

Curebound collaborator: Changlu Liu, PhD, director of Receptor Pharmacology in the Conrad Prebys Center for Chemical Genomics.

Pandurangan Vijayanand

Pandurangan Vijayanand, MD, PhD, is the William K. Bowes Distinguished Professor at the La Jolla Institute for Immunology.

Institute News

AI-driven cancer prediction tool makes NIH director’s highlights for 2024

AuthorScott LaFee
Date

January 3, 2025

illustration of AI driven data

On April 18, 2024, first author Sanju Sinha, PhD, an assistant professor in the Cancer Molecular Therapeutics Program at Sanford Burnham Prebys, and colleagues published details about a new artificial intelligence-powered tool called PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology).

PERCEPTION was proof-of-concept that AI could be used to predict a cancer’s treatment responses from bulk RNA. Sinha and colleagues built AI models for 44 drugs approved by the FDA and found that their tool “predicted the success of targeted treatments against cell lines with a high degree of accuracy.”

The paper was among six specifically highlighted by Monica Bertagnolli, MD, in her blog as director of the National Institutes of Health.

Institute News

Six questions with Lab Manager honoree Sushmitha Vallabh

AuthorGreg Calhoun
Date

December 2, 2024

Sushmitha Vallabh profile photo
Sushmitha Vallabh, a senior lab manager at Sanford Burnham Prebys, was recognized for her outstanding contributions by Lab Manager magazine in October 2024.

Sushmitha Vallabh, a senior lab manager at Sanford Burnham Prebys, was recognized for her outstanding contributions by Lab Manager magazine during the publication’s celebration of Lab Manager Appreciation Month in October 2024.

The magazine encouraged readers to nominate peers who demonstrate exceptional leadership in their labs. The team behind the publication also plans virtual and in-person professional development events for lab managers, as well as offers digital learning and certificate programs through The Lab Manager Academy.

Vallabh works in the lab of Carl Ware, PhD, a professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys. We caught up with Vallabh to discuss this national recognition.

How did you enter the field of lab management?

Before joining Sanford Burnham Prebys, I was at the Cincinnati Children’s Hospital Medical Center. I completed a master’s degree there and then joined the lab I had trained in as a staff member.

I was in that lab for close to four years, and during that time it grew considerably. One of the senior research technicians left, so I took over some of the lab management tasks, such as ordering supplies and making sure protocols were in place.

When I moved to San Diego and applied for a research technician job at my current lab, we ended up discussing my lab management experience. The lab also had a need in that area, so I ended up joining as a lab coordinator in 2020 and being promoted to lab manager the following year.

What do you like most about your role?

I like it when I’m able to solve problems. Every day, I discuss a variety of issues with any number of lab members. I try my best to find solutions for everyone, and it is always fulfilling to be able to answer questions and resolve challenges.

What did it mean to you to be selected for this honor?

I was very, very surprised, but in a good way. It felt especially rewarding because I’ve been following Lab Manager magazine for quite some time now. It is a great organization that provides professional development opportunities for lab managers, so it is nice to be honored by a group doing important work in the field.

What is the most important trait or skill you can help foster to make a lab more successful?

I think training is crucial. Even when new lab members join that have significant research experience, all labs and organizations are different. It is important to train new members on lab standards and protocols in order to set each individual within the lab up for success.

What is the top piece of advice you would give to someone considering entering your field?

Not to react quickly or jump to conclusions. Disagreements and conflicts will happen, and it is always important to talk to everyone involved before determining how best to resolve the situation.

Is there anyone you would like to acknowledge that helped you achieve this honor?

Zumi Alvarado is a lab coordinator at Sanford Burnham Prebys. I have trained her on our standards and protocols to facilitate collaboration between our labs. She thought there were practices she could adapt to her own team, so that must be why she nominated me for this award. It was thoughtful of her to put me in the running for this recognition.

I’m also grateful to Carl as my principal investigator. He has full faith in me, and he’s always there to help if I reach out about a problem. Also, I’d like to thank Paula Norris, the Ware lab’s lab director when I was hired. She was a wonderful mentor as I was learning about the lab.

Institute News

Protein superfamily crucial to the immune system experiences Broadway-style revival

AuthorGreg Calhoun
Date

November 19, 2024

Tumor necrosis factor-α (TNF), shown in pink and tan, is depicted in a complex with an antibody called golimumab, pictured in slate gray
Tumor necrosis factor-α (TNF), shown in pink and tan, is part of a large family of signaling proteins known to play a key role in developing and coordinating the immune system. Here, TNF is depicted in a complex with an antibody called golimumab, pictured in slate gray. Golimumab is used as a drug to treat rheumatoid arthritis and other autoimmune disorders, which it does by smothering the receptors on TNF that initiate inflammation.

More than 25 years after targeting a member of this superfamily of proteins led to groundbreaking treatments for several autoimmune diseases including rheumatoid arthritis and Crohn’s disease, San Diego scientists note a resurgence of interest in research to find related new drug candidates.

In 1998, the same year “Footloose” debuted on Broadway, REMICADE® (infliximab) was approved by the FDA for the treatment of Crohn’s disease. This was the first monoclonal antibody ever used to treat a chronic condition, and it upended the treatment of Crohn’s disease.

Research published in February 2024 demonstrated better outcomes for patients receiving infliximab or similar drugs right after diagnosis rather than in a “step up” fashion after trying other more conservative treatments such as steroids.

Infliximab and ENBREL® (etanercept) — also approved in 1998 to treat rheumatoid arthritis — were the first FDA-approved tumor necrosis factor-α (TNF) inhibitors. TNF is part of a large family of signaling proteins known to play a key role in developing and coordinating the immune system.

The early success of infliximab and etanercept generated excitement among researchers and within the pharmaceutical industry at the possibility of targeting other members of this protein family. They were interested in finding new protein-based (biologics) drugs to alter inflammation that underlies the destructive processes in autoimmune diseases.

As “Footloose” made it back to Broadway in 2024 for the first time since its initial run, therapies targeting the TNF family are in the midst of their own revival. Carl Ware, PhD, a professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys, and collaborators at the La Jolla Institute for Immunology and biotechnology company Inhibrx, report in Nature Reviews Drug Discovery that there is a resurgence of interest and investment in these potential treatments.

“Many of these signaling proteins or their associated receptors are now under clinical investigation,” said Ware. “This includes testing the ability to target them to treat autoimmune and inflammatory diseases, as well as cancer.”

Today, there are seven FDA-approved biologics that target TNF family members to treat autoimmune and inflammatory diseases. There also are three biologics and two chimeric antigen receptor (CAR)-T cell-based therapies targeting TNF members for the treatment of cancer. This number is poised to grow as Ware and his colleagues report on the progress of research and many clinical trials to test new drugs in this field and repurpose currently approved drugs for additional diseases.

“The anticipation levels are high as we await the results of the clinical trials of these first-, second- and — in some cases — third-generation biologics,” said Ware.

Ware and his coauthors also weighed in on the challenges that exist as scientists and drug companies develop therapies targeting the TNF family of proteins, as well as opportunities presented by improvements in technology, computational analysis and clinical trial design.

Portrait of Carl Ware

Carl Ware, PhD, is a professor in the Immunity and Pathogenesis Program at Sanford Burnham Prebys.

“There are still many hurdles to get over before we truly realize the potential of these drugs,” noted Ware. “This includes the creation of more complex biologics that can engage several different proteins simultaneously, and the identification of patient subpopulations whose disease is more likely to depend on the respective proteins being targeted.

“It will be important for researchers to use computational analysis of genetics, biomarkers and phenotypic traits, as well as animal models that mimic these variables. This approach will likely lead to a better understanding of disease mechanisms for different subtypes of autoimmune conditions, inflammatory diseases, and cancer, enabling us to design better clinical trials where teams can identify the appropriate patients for each drug.”

Institute News

The implastic nature of plastic culture

AuthorScott LaFee
Date

November 4, 2024

Cultured cancer cells from the “immortal” HeLa human line. Image courtesy of Matthew Daniels, Wellcome Collection.
Cultured cancer cells, like these from the “immortal” HeLa human line, have proven crucial to basic cancer research. But do they accurately capture the look and behavior of living tumor cells? Kevin Tharp says no, hindering effective drug development. Image courtesy of Matthew Daniels, Wellcome Collection.

There is an art (and science) to creating cell culture models that reflect the complexities of disease. Such models have long been indispensable to parsing the underlying mechanisms of pathology and to preclinical drug discovery.

But art, writes Kevin Tharp, PhD, assistant professor in the Cancer Metabolism and Microenvironment Program, doesn’t always imitate life — at least not when it comes to finding effective cancer therapeutics.

“Just like a machine-learning algorithm trained on irrelevant datasets, efforts to discover anticancer therapeutics are limited by the models we use,” Tharp writes in the British Journal of Pharmacology. “Our drug discovery pipeline works incredibly well but is applied to models that poorly recapitulate in vivo physiology. This may be why drug discovery approaches efficiently identify drugs that work in the context tested and yet often fail to translate into clinical success.”

It’s a case of there’s no place like home. Cancer cell models are cultured on plastic in two-dimensions with limited or no diversity of neighbors. Cancer cells in vivo reside in three dimensions, with dynamic and complex interactions with neighboring cells and surroundings, i.e., the tumor microenvironment.

It’s like growing up on Disneyland’s Main Street versus a real-world urban city. Cultured cancer cells simply don’t look or behave exactly the same as cancer cells in an actual  tumor. Nor do the investigational molecules being tested as potential therapies.

Tharp suggests a multi-pronged approach: Initially culture target cells using conventional methods, then transfer the cells to new culture formats that enforce distinct, non-genomic cytoskeleton architectures and expression patterns that more closed mimic real life.

Institute News

Raising awareness of breast cancer research at Sanford Burnham Prebys

AuthorGreg Calhoun
Date

October 31, 2024

Kelly Kersten, PhD, and Kevin Tharp, PhD

The October Science Connect Series event was themed around Breast Cancer Awareness Month and featured two cancer research experts.

The Sanford Burnham Prebys Wellness Ambassadors hosted a Science Connect event on Wednesday, October 30, 2024, featuring two faculty experts discussing their breast cancer research and its implications.

The Science Connect Series provides a forum for Sanford Burnham Prebys principal investigators to share their research with administrative personnel. Faculty members gain experience in communicating their science to a lay audience, and administrators gain a better understanding of research conducted at the institute so they can become better advocates and ambassadors of the shared mission to translate science into health.

Kelly Kersten, PhD, an assistant professor in the Cancer Metabolism and Microenvironment Program, opened the event by focusing on the importance of finding new treatments —such as immunotherapies — for the one-third of breast cancer patients that are diagnosed after the early stages of the disease when surgery is less effective.

The immune system is one of the main defenses of the human body to fend off harmful pathogens and invasive cells, such as cancer. Among all white blood cells, a particular cell type, called a T cell, can directly kill cancer cells and therefore plays an essential role in building anti-tumor immune responses.

Many types of cancer are confronted and infiltrated by T cells, only to be suppressed by the local tumor environment.

“While immunotherapies that boost the immune system have revolutionized the way we treat cancer, many patients do not respond to the treatments, and the mechanisms of resistance remain largely unclear,” said Kersten.

Kersten’s goal is to understand why T cells enter a state known as exhaustion and lose their tumor-killing capacity. This knowledge will help her team find potential future therapies that could prevent T-cell exhaustion and improve immunotherapies for cancer patients.

Kevin Tharp, PhD, also an assistant professor in the Cancer Metabolism and Microenvironment Program, shared that his lab’s focus is on how cancer cells adapt their metabolism to generate the energy needed to spread to other tissues through metastasis. He presented his team’s work with the Kersten lab on another aspect of potential resistance to immunotherapy in breast cancer.

Tharp and Kersten are studying the hypothesis that part of the reason why these therapies fail is due to tumor-associated fibrosis, the creation of a thick layer of fibrous collagen (like scar tissue) that acts as a barrier against the anti-tumor immune response. They published a paper on June 3, 2024, in Nature Cancer,  discussing how tumor-associated macrophages, a type of immune cell found abundantly in the tumor microenvironment, respond to the physical properties of fibrosis.

By synthesizing injury-associated collagens that facilitate wound closure, TAMs experience metabolic changes and generate metabolic byproducts that suppress the anti-tumor function of immune cells.

“The metabolic changes in the microenvironment present more of a challenge to anti-tumor responses than the physical barrier,” said Tharp. “Our study provides an alternative explanation for why anti-tumor immunity is impaired in fibrotic solid tumors.”

To follow up on these results, Tharp is collaborating with Sarah Blair, MD, a professor of surgery at the University of California San Diego, to fund and initiate a clinical trial testing the potential of dietary supplements to counteract the suppressive effects of TAM metabolic byproducts as an adjunct therapy to surgery.

Institute News

Two Sanford Burnham Prebys scientists selected for American Cancer Society postdoctoral fellowships

AuthorGreg Calhoun
Date

October 18, 2024

combined photos of Alicia Llorente Lope and Ambroise Manteau
Alicia Llorente Lope, PhD, is a postdoctoral associate in the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. Ambroise Manceau, PhD, is a postdoctoral associate in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center.

Funds will support Alicia Llorente Lope and Ambroise Manceau who study breast and pancreatic cancer

Alicia Llorente Lope, PhD, and Ambroise Manceau, PhD, were awarded 2024 Postdoctoral Fellowships from the American Cancer Society (ACS). These prestigious awards provide more than $65,000 per year for up to three years to support early career scientists studying cancer.

“I was so excited when I heard the news,” said Llorente. “It is a privilege to have this award, and it feels very validating to know that someone saw enough potential in my research to deem it worthy of funding.”

Tackling treatment-resistant breast cancer

Llorente joined the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, nearly three years ago after beginning her breast cancer research career as a doctoral student.

“I was first interested in breast cancer because my grandmother died of the disease, and I wanted to contribute to finding new therapeutic opportunities for cancer patients,” said Llorente. Llorente’s ACS-funded research project focuses on HER2-positive (HER2+) breast cancer.

Roughly one in five breast cancer tumors have elevated levels of the HER2 protein. While these tumors tend to grow quickly, drugs targeting the HER2 protein are usually effective at first. However, HER2+ tumors often are able to adapt and develop resistance to these drugs over time, leaving patients with few if any remaining treatments options.

Llorente has found evidence that a form of the protein phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) plays a role in breast cancer tumors becoming resistant to HER2 drugs.

Brooke Emerling

Brooke Emerling, PhD

“We’ve revealed a strong connection between elevated levels of PI5P4K gamma and reduced survival rates in patients with HER2+ breast cancer,” explained Llorente. “I plan to explore whether targeting both HER2 and PI5P4K gamma in breast cancer cells may provide a path to overcoming treatment resistance.” Llorente also will study the functions of PI5P4K gamma in breast cancer cells to see why these cells cease to respond to HER2-targeting drugs.

“I am incredibly proud of Alicia for spearheading this groundbreaking project targeting the lipid kinase PI5P4K gamma,” said Emerling. “Her insightful analysis of breast cancer datasets, which uncovered a correlation between elevated expression of PI5P4K gamma and worse outcomes in HER2+ patients, has set the stage for vital research aimed at overcoming the significant challenge of resistance to targeted therapies in HER2+ tumors.”

Cosimo Commisso headshot

Cosimo Commisso, PhD

Powering down pancreatic cancer

Manceau is in the second year of his postdoctoral training in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center. During his doctoral program, Manceau studied how abnormal cells die in a programmed series of steps called apoptosis, a process known to go awry in cancer and neurodegenerative diseases.

“It began as a basic science project about the molecular processes around cell death, and over time it led to possible therapeutic implications,” said Manceau. “I learned that I like to study fundamental biology and then try to find an application for it, and I saw in the Commisso lab an opportunity to do just that in pancreatic cancer.”

Manceau’s fellowship project focuses on pancreatic ductal adenocarcinoma (PDAC) — the most common form of pancreatic cancer with only a 13% five-year survival rate — and its ravenous pursuit of energy. Because of PDAC cells’ constant need for fuel to sustain their rampant growth, they adapt by reshaping the surface of their cells to snatch extra nutrients from the jelly-like substance between cells.

Commisso and others have shown that cutting off the extra power supplied by this process — known as macropinocytosis — reduces tumor growth. Manceau has studied the contents taken by contorted pancreatic cell surfaces in pockets called macropinosomes. By analyzing every single protein in this scooped goop, he found that calcium transporter proteins present in macropinosomes also are required for macropinocytosis.

“During the fellowship, I will work to understand how these transporter proteins affect macropinocytosis,” said Manceau. “These proteins have never been targeted before in pancreatic cancer, so our long-term goal is to use this strategy to cut the nutrient supply to tumors and see if we can inhibit tumor growth.”

“By disrupting the cancer cells’ ability to feed themselves through macropinocytosis, we can potentially starve tumors and inhibit their growth,” added Commisso. “Ambroise’s research aims to target key proteins involved in this process, opening up new possibilities for treatments that could significantly improve outcomes for patients battling pancreatic cancer.”

Institute News

How a protein component of nuclear pore complexes regulates development of blood cells and may contribute to myeloid disorders

AuthorCommunications
Date

June 5, 2024

A computer graphic depicts a nuclear pore in a eukaryotic cell. Nuclear pores are large protein complexes that span the nuclear membrane and allow the movement of molecules, such as proteins, RNAs, and other molecules between the nucleus and the cell’s cytoplasm. Image courtesy of M. Towler and J. Aitken, Wellcome Collection.
Computer graphic depicts a nuclear pore in a eukaryotic cell. Nuclear pores are large protein complexes that span the nuclear membrane & allow the movement of molecules, such as proteins, RNAs, & other molecules between the nucleus & the cell’s cytoplasm.

Nuclear pore complexes (NPCs) are channels composed of multiple proteins that ferry molecules in and out of the nucleus, regulating many critical cellular functions, such as gene expression, chromatin organization and RNA processes that influence cell survival, proliferation, and differentiation.

In recent years, new studies, including work by Maximiliano D’Angelo, PhD, associate professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, have noted that NPCs in cancer cells are different, but how these alterations contribute to malignancy and tumor development—or even how NPCs function in normal cells—is poorly understood.

In a new paper, published June 5, 2024 in Science Advances, D’Angelo with first author Valeria Guglielmi, PhD, and co-author Davina Lam, uncover Nup358, one of roughly 30 proteins that form the NPCs, as an early player in the development of myeloid cells, blood cells that if not formed or working properly leads to myeloid disorders such as leukemias.

The researchers found that when they eliminated Nup358 in a mouse model, the animals experienced a severe loss of mature myeloid cells, a group of critical immune cells responsible for fighting pathogens that are also responsible for several human diseases including cancer. Notably, Nup358 deficient mice showed an abnormal accumulation of early progenitors of myeloid cells referred as myeloid-primed multipotent progenitors (MPPs).

“MPPs are one of the earliest precursors of blood cells,” said D’Angelo. “They are produced in the bone marrow from hematopoietic stem cells, and they differentiate to generate the different types of blood cells.

Maximiliano D’Angelo and Valeria Guglielmi

“There are different populations of MPPs that are responsible for producing specific blood cells and we found that in the absence of Nup358, the MPPs that generate myeloid cells, which include red blood cells and key components of the immune system, get stuck in the differentiation process.”

Fundamentally, said Gugliemi, Nup358 has a critical function in the early stages of myelopoiesis (the production of myeloid cells). “This is a very important finding because it provides insights into how blood cells develop, and can help to establish how alterations in Nup358 contribute to blood malignancies.”

The findings fit into D’Angelo’s ongoing research to elucidate the critical responsibilities of NPCs in healthy cells and how alterations to them contribute to immune dysfunction and the development and progression of cancer.

“Our long-term goal is to develop novel therapies targeting transport machinery like NPCs,” said D’Angelo, who recently received a two-year, $300,000 Discovery Grant from the American Cancer Society to advance his work.

This research was supported in part by a Research Scholar Grant from the American Cancer Society (RSG-17-148-01), the Department of Defense (grant W81XWH-20-1-0212) and the National Institutes of Health (AI148668).

The study’s DOI is 10.1126/sciadv.adn8963.