Abstract B001: Cancer-associated fibroblast p38α MAPK signaling coordinates collagen architecture and immune suppression to drive chemoresistance in pancreatic cancer
Camille M. Acevedo, Sayan Chakraborty, Samara Singh, Edmond W. Box, Andrew M. Adams, Karthik Rajkumar, Haleh Amirian, Jashodeep Datta, Nagaraj Nagathihalli, Austin Dosch, Nipun B. MerchantAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to chemoimmunotherapy due in large part to its dense, immunosuppressive stroma. Cancer-associated fibroblasts (CAFs), the dominant stromal cell population, promote tumor progression through inflammatory signaling, aligned collagen-rich extracellular matrix (ECM), and immune exclusion. Broad-based CAF depletion strategies have failed clinically, underscoring the need to selectively target pro-tumorigenic CAF functions. We identified p38α MAPK (p38α; MAPK14) as a key regulator of inflammatory CAF activation and collagen remodeling. p38α signaling is further induced in stroma-rich patient tumors and following treatment with chemotherapy, implicating it as a central mediator of stromal remodeling and therapeutic resistance.
Methods:
Human and murine CAFs underwent pharmacologic inhibition or CRISPR-Cas9-mediated deletion of MAPK14. Inflammatory and matrix programs were assessed by RNA sequencing, cytokine profiling, and collagen fiber angle-orientation analysis. Tumor-cell proliferation, invasion, mechanosensing, and focal-adhesion formation were evaluated in co-culture and on decellularized CAF-derived matrices. An inducible fibroblast-specific Col1a2 Cre/ERT2;Mapk14 flox/flox (CAF-p38 KO) mouse model was generated and used with orthotopic PDAC tumors to evaluate tumor burden, stromal architecture, immune composition, and response to gemcitabine/paclitaxel chemotherapy.
Results:
MAPK14-dependent signaling was enriched in fibroblast-rich human PDAC and was further activated in CAFs by chemotherapy. Genetic deletion or pharmacologic inhibition of p38α in CAFs concordantly suppressed IL6 secretion and myeloid chemoattraction, reduced extracellular-matrix programs, and decreased collagen alignment. Tumor cells exposed to p38α-deficient CAFs or their decellularized matrices exhibited impaired proliferation and invasion, reduced mechanosensing, and fewer paxillin-positive focal adhesions. In vivo, fibroblast-specific Mapk14 deletion reduced orthotopic tumor burden, attenuated inflammatory CAF programs, and decreased collagen deposition. Flow cytometry demonstrated fewer total, monocytic, and polymorphonuclear myeloid-derived suppressor cells, increased cytotoxic T cell infiltration, and reduced regulatory T cells, consistent with stromal reprogramming towards a tumor-restraining phenotype. Strikingly, treatment with chemotherapy increased CAF p38α activation, inflammatory CAF abundance, and intratumoral fibrosis. CAF-p38 KO mice treated with chemotherapy demonstrated significantly improved survival compared to control mice.
Conclusion:
CAF-intrinsic p38α MAPK coordinates inflammatory signaling, collagen architecture, and tumor mechanotransduction to establish an immune-suppressive, treatment-resistant PDAC microenvironment. Selective p38α disruption reprograms rather than depletes fibroblasts and enhances chemotherapy efficacy, identifying a rational stromal therapeutic strategy.
Citation Format:
Camille M. Acevedo, Sayan Chakraborty, Samara Singh, Edmond W. Box, Andrew M. Adams, Karthik Rajkumar, Haleh Amirian, Jashodeep Datta, Nagaraj Nagathihalli, Austin Dosch, Nipun B. Merchant. Cancer-associated fibroblast p38α MAPK signaling coordinates collagen architecture and immune suppression to drive chemoresistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B001.