Thursday, April 3, 2025
4/3/2025
Endoplasmic Reticulum Stress in the function of cancer associated fibroblasts in pancreatic cancer - ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a dismal 5-year overall survival of 13%. Among the reasons for such a poor outlook is the presence of a highly fibrotic and immunosuppressive microenvironment, characterized by activation and expansion of fibroblasts and their extracellular matrix (ECM). During PDAC development, cancer-associated fibroblasts (CAFs) produce large amounts of ECM, cytokines, chemokines and growth factors, and despite their pivotal pro-tumor roles, the drivers of their activation and pro- tumor functions are still unknown. Paradoxically, elimination of CAFs and their ECM is unfavorable to patients, suggesting that modulation, rather than elimination, of pro-tumor CAFs, is an innovative and attractive approach in developing PDAC therapies. CAFs are highly secretory cells, which increases the load of misfolded proteins in the endoplasmic reticulum (ER). Accordingly, our preliminary data uncovered that CAFs, compared to normal fibroblasts, are under ER stress, upregulating sensors (IRE1, PERK and ATF6) and downstream effectors of the unfolded protein response. When blocking these pathways with chemical inhibitors, CAFs produced less immunosuppressive cytokines compared to vehicle treated CAFs, which in turn, allowed CD8+ T cells to proliferate more when cultured with ER stress-inhibited CAFs. Finally, in a preliminary orthotopic syngeneic model, mice treated with the inhibitor of the ER stress effector XBP1 had smaller tumors and higher percentage of CD8+ T cells compared to control mice. These results led us to hypothesize that ER stress promotes and sustains CAF pro-tumor functions, catalyzing PDAC tumorigenesis. In an innovative approach, here we propose to investigate the roles of ER stress in fibroblast activation and function in PDAC, dissecting the contributions of the different ER stress arms for their pro-tumor functions. Our long-term goal is to uncover new targets that can modulate PDAC microenvironment to sensitize tumors to therapies. Using state of the art in vitro 3D culture system, bona-fide normal donor pancreata and patient PDAC tissue for spatial transcriptomics, and refined in vivo animal models, we will focus on 1) dissecting the roles of ER stress on the pro-tumor functions of fibroblasts, 2) determine the spatial distribution and functional relevance of ER stress in donor normal and PDAC tissue, 3) test if specific arms of ER stress in CAFs promotes tumorigenesis in vivo. This study will not only determine the roles of ER stress in fibroblast functions in PDAC, but also provide new insights into CAF biology in PDAC by providing a framework to link common functional programs of different subsets of cells in the TME that coevolve during tumor progression.
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