Pancreatic cancer-associated fibroblasts: function, detection, and regulation

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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 NetrinG1. Of note, NetrinG1 necessities co-receptors in cis and in trans to signal and we revealed that in response to ECM NetrinG1 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 (a-α5), which we posit regulates the production of two unique extracellular vesicles. Finally, we saw that the trans co-receptor of NetrinG1 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 NetrinG1 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 NetrinG1 expression and endocytic a-α5 regulation as well as what are the specific ECM components that are responsible for NetrinG1 expression and CAF’s pro-tumor function. 2- Investigate if the unique extracellular vesicles generated by NetrinG1 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 NetrinG1’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 systemically induce and detect a pro-to-anti pancreatic cancer CAF transition, which could be indicative of local desmoplastic status, for potential future clinical uses.