Cancer Metabolism and Microenvironment Program

intestinal epithelia

How does the sum of the parts in a tumor make up the whole?

Just like a complex machine is made up of synchronized parts, cancer is the sum of highly organized cells and molecules that relay information causing the tumor to grow.

Our scientists have come together to coalesce around the goal of understanding how nutrients and the tumor microenvironment interact to control how a tumor forms, grows, and spreads. From individual metabolites to stromal cells, such as fibroblasts and immune cells, our goal is to understand how the fundamental parts of a tumor work together to cause disease. This comprehensive view of cancer biology guides the way we study tumor progression, and our approach to discovering new therapies.

Director's statement

Our investigators focus on understanding how the tumor ecosystem impacts tumor initiation, progression, and therapy. We study fundamental processes in cancer, including metabolism, signal transduction, tumor-stroma crosstalk, and molecular machines. We want to know what the different parts of a tumor 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

Scientific highlights

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.


Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death.

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

PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay.

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

Mechanical stress through growth on stiffer substrates impacts animal health and longevity in C. elegans.

Oorloff M, Hruby A, Averbukh M, Alcala A, Dutta N, Torres TC, Moaddeli D, Vega M, Kim J, Bong A, Coakley AJ, Hicks D, Wang J, Wang T, Hoang S, Tharp KM, Garcia G, Higuchi-Sanabria R

bioRxiv 2024 Apr 12 ;

TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.

Hao X, Zhao B, Towers M, Liao L, Monteiro EL, Xu X, Freeman C, Peng H, Tang HY, Havas A, Kossenkov AV, Berger SL, Adams PD, Speicher DW, Schultz D, Marmorstein R, Zaret KS, Zhang R

Nat Aging 2024 Feb ;4(2):185-197

Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.

Recouvreux MV, Grenier SF, Zhang Y, Esparza E, Lambies G, Galapate CM, Maganti S, Duong-Polk K, Bhullar D, Naeem R, Scott DA, Lowy AM, Tiriac H, Commisso C

Nat Cancer 2024 Jan ;5(1):100-113

Chemoresistance in pancreatic ductal adenocarcinoma: Overcoming resistance to therapy.

Bhoopathi P, Mannangatti P, Das SK, Fisher PB, Emdad L

Adv Cancer Res 2023 ;159:285-341

PSGL-1 attenuates early TCR signaling to suppress CD8(+) T cell progenitor differentiation and elicit terminal CD8(+) T cell exhaustion.

Hope JL, Otero DC, Bae EA, Stairiker CJ, Palete AB, Faso HA, Lin M, Henriquez ML, Roy S, Seo H, Lei X, Wang ES, Chow S, Tinoco R, Daniels GA, Yip K, Campos AR, Yin J, Adams PD, Rao A, Bradley LM

Cell Rep 2023 May 30 ;42(5):112436

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