Understanding the accomplice cells that help drive pancreatic cancer

Mara Sherman’s award-winning research is uncovering the role of non-cancer cells that support tumor growth in pancreatic ductal adenocarcinoma.

The pancreatic cancer survival rate, averaging around 9 percent at five years, is the worst among major cancers. Mara Sherman, Ph.D., is aiming to improve outcomes with a better understanding of the role of the non-cancer cells that support tumor growth in pancreatic ductal adenocarcinoma.

Image: A cluster of pancreatic cancer cells viewed by scanning electron microscopy (Anne Weston/Francis Crick Institute via the Wellcome Collection)Sherman is one of five leading early-career cancer scientists across the U.S. named as a Pew-Stewart Scholar for Cancer Research, an award that provides $300,000 over four years. Sherman is an assistant professor of cell, developmental and cancer biology in the OHSU School of Medicine and co-leader of the Cancer Biology Program in the Knight Cancer Institute.

Mara Sherman, Ph.D.

“When you look at these pancreatic tumors, you see that a small minority of the tumor area is cancer cells; the rest is fibrous tissue generated in a scar-like reaction by cells called cancer-associated fibroblasts,” Sherman says. “We don’t know enough about the scar-like reaction. Understanding it is really going to be crucial to help us developing new therapies.”

The dense growth of fibrous tissue is one of the factors that makes pancreatic cancer difficult to treat. Cells within give support that helps tumors grow. And the dense matrix limits blood flow and the delivery of therapeutic drugs. Therapies that directly target the cancer-associated fibroblasts, or CAFs, have been attempted and haven’t work in clinical trials, Sherman says, highlighting need for a much deeper understanding of the biology.

CAFs are thought to arise from lipid-storing stellate cells in healthy pancreas. But no studies have ever proven that stellate cells are the main source of CAFs. “Our work suggests this is not in fact that case,” Sherman says.

The Sherman lab has established a mouse model in which fluorescent labels can be used to track the trajectories of cells during tumor development as cells divide into different lineages. “We’ve also devised a way to engineer the system so we can specifically delete subsets of these environmental cells and analyze the impact on tumors,” Sherman says.

Preliminary data suggest that the stellate cells give rise to only a subset CAFs in and around tumors. The functions of the different subsets are unknown. Sherman’s model system will allow her lab to analyze the distinguishing features of CAF subpopulations from disparate origins, and determine the significance of genetic alterations on the fate of non-cancer cells and their functions.

“This is really important because a number of previous studies have made the surprising finding that if you completely, broadly ablate CAFs, it actually makes tumors more aggressive and shortens survival, which conflicts with studies showing that CAFs support tumor growth,” Sherman says. “We need to go in and do the hard work of picking apart this complex population of cells, understand the distinct functions of CAF subsets and the specific mechanisms that drive tumor growth.”

Further reading:

Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment by Erin Helms, M. Kathrina Onate and Mara H. Sherman. Cancer Discovery (May 2020)

A Framework for Advancing Our Understanding of Cancer-Associated Fibroblasts by
Erik Sahai, Igor Astsaturov, Zena Werb and others. Nature Reviews Cancer (January 24, 2020)

Fibroblasts as Modulators of Local and Systemic Cancer Metabolism by Hannah Sanford-Crane, Jaime Abrego and Mara H. Sherman. Cancers (May 3, 2019)