R01CA269660

Pancreatic Cancer-Associated Fibroblasts: Function, Detection, and Regulation - Project Summary/Abstract

Pancreatic cancer induces a fibrous microenvironment, desmoplasia, which spans most of the tumor mass and contains cancer-associated fibroblasts (CAFs). CAFs sustain a cancer homeostatic equilibrium by producing extracellular matrices (ECMs) and secreting inflammatory factors. The ECM produced by CAFs prompts normal fibroblasts to undergo activation and transition into CAFs, thereby propagating desmoplastic expansion in a positive feedback loop. While the normal microenvironment suppresses tumor onset, desmoplasia can either support or avert pancreatic cancer.

A better understanding of desmoplastic expansion and the ECM factors that control it could enable us to favor its anti-cancer functions. In fact, several clinical trials, including some conducted at Fox Chase, aim at "normalizing desmoplasia" with the goal of harnessing CAF's anti-tumor effects. Of note, we have defined a signaling axis that depends on CAF-ECM and includes its main receptors, integrins, and some actin bundling, particular endocytic regulatory proteins, and an extracellularly tethered presynaptic protein known as netrin-1.

Of note, netrin-1 necessitates co-receptors in cis and in trans to signal, and we revealed that in response to ECM, netrin-1 drives pro-tumor CAF function. We also reported that ECM-induced pro-tumor CAF activation includes the endocytic localization of the active conformation of an important ECM receptor, activated α5β1-integrin (α5β1), which we posit regulates the production of two unique extracellular vesicles. Finally, we saw that the trans co-receptor of netrin-1 is expressed in CAFs and needed for effective formation of tumors when pancreatic cancer cells are injected into the pancreata of immune system-intact mice.

Our central premise proposes that CAF pro-to-anti tumor function transition can be attained via blockage of the ECM-dependent netrin-1 signaling axis, which is needed to achieve the functional "desmoplastic normalization" that can be detected in blood. We plan to test this hypothesis in three specific aims:

1. Ask how CAF-ECM regulates netrin-1 expression and endocytic α5β1 regulation, as well as what are the specific ECM components that are responsible for netrin-1 expression and CAF's pro-tumor function.

2. Investigate if the unique extracellular vesicles generated by netrin-1-expressing CAFs could be traced systemically in patients' blood (including archived samples and samples from the ongoing trial) and ask if these are indicative of the tumor-associated desmoplastic pro vs anti-pancreatic cancer statuses.

3. Inquire if netrin-1's trans receptor, expressed in pro-tumoral functioning CAFs, could serve as a new target.

The study's ultimate goal is to capitalize on the natural tumor suppressive function and features of CAFs and block the tumor-promoting ones, as well as to systematically induce and detect a pro-to-anti pancreatic cancer CAF transition, which could be indicative of local desmoplastic status, for potential future clinical uses.

The Institute For Cancer Research

NOT APPLICABLE

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Philadelphia, Pennsylvania 191112434 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 496% from $517,107 to $3,080,613.