Abstract A006: A p38α MAPK-TCF21 axis regulates pancreatic stellate cell activation and stromal reprogramming in pancreatic cancer
Sayan Chakraborty, Camille Acevedo, Samara Singh, Edmond W. Box, Andrew Adams, Karthik Rajkumar, Varunkumar Krishnamoorthy, Jashodeep Datta, Nagaraj Nagathihalli, Austin Dosch, Nipun B. MerchantAbstract
Background:
Pancreatic stellate cells (PSCs) are a principal source of cancer-associated fibroblasts (CAF) in pancreatic ductal adenocarcinoma (PDAC), yet the mechanisms that convert tumor-derived inflammatory cues into a persistent, CAF-like state remain poorly defined. We previously identified tumor cell-intrinsic p38α MAPK (MAPK14) as a driver of IL1α-dependent stromal inflammation. Given its central role in integrating cellular stress and inflammatory signals, we investigated whether p38α acts as a key regulator of PSC activation and stromal reprogramming in PDAC.
Methods:
Human PSCs were exposed to interleukin-1α (IL-1α) or PDAC cell- conditioned media (CM) following pharmacologic inhibition or CRISPR-Cas9-mediated MAPK14 deletion. Cell state, signaling and secretory function were evaluated by immunoblotting, quantitative PCR, immunofluorescence, flow cytometry, and cytokine analysis. Bulk RNA sequencing and ATAC sequencing along with pathway and transcription factor motif analyses were integrated with human and murine PDAC transcriptomic datasets and human single-cell RNA sequencing data. TCF21 was functionally evaluated by small interfering RNA-mediated silencing.
Results:
MAPK14-dependent programs were enriched in stroma-high PDAC and localized predominantly to fibroblasts in Human Tumor Atlas Network datasets. IL-1α or tumor CM activated p38α activation, reduced quiescent PSC markers FABP4 and Desmin, and increased PDGFRα, PDPN, and α-SMA. Activated PSCs secreted increased IL-6, CXCL1, CXCL2, and CXCL8. In contrast, pharmacologic inhibition and MAPK14 deletion preserved PSC quiescence and attenuated inflammatory activation, despite continued stimulation. RNA sequencing showed suppression of inflammatory, profibrotic, and extracellular matrix programs after p38α inhibition. These effects occurred without measurable changes in NF-κB activation or p65 DNA binding. ATAC-sequencing identified p38α-dependent chromatin remodeling at inflammatory regulatory loci and motif analysis identified TCF21 as a potential transcriptional mediator. TCF21 expression correlated with stromal enrichment and MAPK14 activity in human PDAC patient datasets, increased after tumor-derived stimulation, and decreased after pharmacologic inhibition or genetic deletion of p38α. TCF21 knockdown phenocopied p38α blockade, increasing FABP4 and desmin while reducing IL6 despite inflammatory stimulation.
Conclusions:
These findings establish fibroblast-intrinsic p38α MAPK as a central regulator of the early PSC-to-CAF transition, coupling inflammatory and tumor-derived signals to chromatin remodeling and sustained stromal activation. TCF21 emerges as a candidate downstream mediator of this p38α-dependent program. Selective disruption of the p38α axis may therefore reprogram pathogenic fibroblast states without indiscriminate stromal depletion, providing a mechanistically informed strategy to limit desmoplastic evolution and enhance therapeutic sensitivity in PDAC.
Citation Format:
Sayan Chakraborty, Camille Acevedo, Samara Singh, Edmond W. Box, Andrew Adams, Karthik Rajkumar, Varunkumar Krishnamoorthy, Jashodeep Datta, Nagaraj Nagathihalli, Austin Dosch, Nipun B. Merchant. A p38α MAPK-TCF21 axis regulates pancreatic stellate cell activation and stromal reprogramming 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 A006.