How do the sum of the parts in a cancer cell make up the whole?
Just like a complex machine is made up of synchronized parts, a cancer cell is the sum of highly organized molecules and compartments that relay information to make a tumor.
Our scientists have come together to coalesce around the goal of understanding how a cancer cell functions from the perspectives of molecular and cellular biology. From individual molecules to organelles, our goal is to understand how the fundamental parts of a human cell work together to support health, and how they malfunction to cause disease. This elemental view of biology guides the way we study cancer, the methods we use to understand it, and our approach to discovering new therapies.
Our investigators focus on understanding how the molecular framework of a cancer cell functions in unison to promote the fundamental processes of metabolism, signaling across membranes, organelle function and cellular vitality. We want to know what parts do, how they work and what they look like. This approach is driving our research toward therapies that target cancer and improve our health.
– Cosimo Commisso, Ph.D., Program Director
Scientists kill cancer cells by “shutting the door” to the nucleus
Because cancer cells are highly dependent on the nuclear transport process—the movement of molecules through nuclear pores—targeting the nuclear transport machinery is a promising strategy for cancer therapies. Targeting the formation of nuclear pore complexes, which only impacts dividing cells and thus would likely only kill cancer cells, may offer a safe way to treat many cancer types. In a recent study published in Cancer Discovery, the Dr. Maximiliano D’Angelo’s lab tested this hypothesis by transplanting human tumor cells that are unable to form nuclear pore complexes into mice. Three different tumor cell types were tested—melanoma, leukemia and colorectal cancer—which are known to be especially reliant on nuclear pore complexes. The scientists found that all of these mice had smaller tumors and slower tumor growth. They showed that the inability to build nuclear pore channels is devastating for rapidly-growing cancer cells, but doesn’t seem to have an impact on healthy cells—which simply halt their growth, and then recover. Their findings provide an important proof of concept that this approach could lead to a new type of cancer treatment, which might be especially beneficial for aggressive or metastatic cancers that are difficult to treat.
Researchers reveal the internal signals cells use to maintain energy
For years scientists have tried to halt cancer by blocking nutrients from reaching tumor cells. But these attempts have been disappointing because cancer cells can adapt and create back up routes to source food to sustain their growth. One promising approach is to find and attack metabolic vulnerabilities within cells, which would deprive them of energy even in an abundance of nutrients and special tactics. In a recent study published in Developmental Cell, Dr. Brooke Emerling’s lab revealed that PI5P4Ks produce an active messenger that coordinates communications between peroxisomes and mitochondria—two organelles intimately involved in making and using fuel to support cellular growth. In the absence of the messenger, the interplay between the organelles breaks down, mitochondria become overworked, and cells starve and die. The scientists use sarcomas as a tumor model because PI5P4Ks are highly expressed in high grade sarcomas, and their expression correlates with patient survival. This research supports targeting PI5P4Ks as a cancer treatment strategy because it would deprive tumors of the one thing they can’t live without: energy.
Scientists shrink pancreatic tumors by starving stromal cells
Pancreatic cancer remains one of the deadliest cancers. Only one in ten people survive longer than five years, and its incidence is on the rise. Pancreatic tumors are surrounded by an unusually thick layer of stroma, or glue-like connective tissue that holds cells together. This stromal barrier makes it difficult for treatments to reach the tumor, and fuels tumor growth by providing the tumor with nutrients. In a recent study published in Cancer Discovery, Dr. Cosimo Commisso’s lab demonstrated for the first time that blocking “cell drinking,” or macropinocytosis, in the thick tissue surrounding a pancreatic tumor slowed tumor growth—providing more evidence that macropinocytosis is a driver of pancreatic cancer growth and is an important therapeutic target. The scientists deciphered the molecular signals that drive macropinocytosis in the stroma, providing new therapeutic avenues for pancreatic cancer researchers to explore. Macropinocytosis is a very important growth driver for many different cancer types and continued efforts to discover a drug that targets macropinocytosis may be the breakthrough needed to finally put an end to many deadly and devastating cancers.
Sakuma S, Raices M, Borlido J, Guglielmi V, Zhu EYS, D'Angelo MA
Cancer Discov 2021 Jan ;11(1):176-193
Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness.
Zhang Y, Recouvreux MV, Jung M, Galenkamp KMO, Li Y, Zagnitko O, Scott DA, Lowy AM, Commisso C
Cancer Discov 2021 Jul ;11(7):1808-1825
Ravi A, Palamiuc L, Loughran RM, Triscott J, Arora GK, Kumar A, Tieu V, Pauli C, Reist M, Lew RJ, Houlihan SL, Fellmann C, Metallo C, Rubin MA, Emerling BM
Dev Cell 2021 Jun 7 ;56(11):1661-1676.e10
Coagulation factor protein abundance in the pre-septic state predicts coagulopathic activities that arise during late-stage murine sepsis.
Heithoff DM, Pimienta G, Mahan SP, Yang WH, Le DT, House JK, Marth JD, Smith JW, Mahan MJ
EBioMedicine 2022 Apr ;78:103965
S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson's Disease and Lewy Body Dementia.
Oh CK, Dolatabadi N, Cieplak P, Diaz-Meco MT, Moscat J, Nolan JP, Nakamura T, Lipton SA
J Neurosci 2022 Apr 6 ;42(14):3011-3024
Zhi J, Yi J, Hou X, Wang W, Yang W, Hu L, Huang J, Guo S, Ruan X, Gao M, Zheng X
Am J Cancer Res 2022 ;12(1):247-264
Reduced MHC class II expression in medullary thyroid cancer identifies patients with poor prognosis.
Ruan X, Yi J, Hu L, Zhi J, Zeng Y, Hou X, Huang J, Gu P, Hao W, Gao M, Pan Y, Wei S, Zheng X
Endocr Relat Cancer 2022 Jan 20 ;29(2):87-98
Synthesis and preliminary studies of (11)C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2.
Zhang X, Zhang Y, Chen Z, Shao T, Van R, Kumata K, Deng X, Fu H, Yamasaki T, Rong J, Hu K, Hatori A, Xie L, Yu Q, Ye W, Xu H, Sheffler DJ, Cosford NDP, Shao Y, Tang P, Wang L, Zhang MR, Liang SH
Theranostics 2020 ;10(24):11178-11196
Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[(11)C]methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu(2)).
Yamasaki T, Zhang X, Kumata K, Zhang Y, Deng X, Fujinaga M, Chen Z, Mori W, Hu K, Wakizaka H, Hatori A, Xie L, Ogawa M, Nengaki N, Van R, Shao Y, Sheffler DJ, Cosford NDP, Liang SH, Zhang MR
J Med Chem 2020 Oct 22 ;63(20):11469-11483