Abstract 1741: STAT3 Orchestrates common and divergent mechanisms in different cell types to promote pancreatic cancer development and progression

Abstract Pancreatic adenocarcinoma (PDAC) is a major healthcare challenge. Currently, there are no good treatments for PDAC, and patient survival is dismal. In vitro and in vivo models to study PDAC pathogenesis have shed some light on the molecular and cellular landscape of the disease, including the prevalence of altered signal transducer and activator of transcription 3 (STAT3) functions. While constitutively-active STAT3 is implicated in PDAC progression, its functional role in driving PDAC development is not fully understood. Using human PDAC (hPDAC) cell lines, hPDAC-derived cancer-associated fibroblasts (hCAFs), and high-fat diet (HFD)-fed mutant KrasG12D (KC) mice, we interrogated aberrantly-active STAT3 and its cell-type specificity to delineate STAT3’s role in PDAC development and therapeutic response. Human PDAC cell lines (AsPC-1, Mia-PaCa-2, and PANC-1) and hCAFs harbor constitutively-active STAT3, and their stimulation with IL-6, EGF or PDGF further enhanced the phospho-tyrosine-STAT3 (pYSTAT3) levels. In KC mice, feeding a HFD led to constitutive pYSTAT3 induction in the pancreas in parallel with the development of precancerous pancreatic intraepithelial neoplasia (PanIN) lesions. Induction of pYSTAT3 occurred across diverse cell types, including acinar-ductal-metaplasia (ADM) elements, neoplastic ducts, stromal and immune cells, but not in acinar cells. Treatment with the STAT3 inhibitor, H182, blocked the pYSTAT3 levels in the hCAFs and hPDAC cells in vitro. Significant profile changes for IL-6-stimulated cytokine and chemokine secretion were also observed, including decreased IL-8, SERPINE1, CXCL1, CXCL12, CCL2 and MIF secretion. Mia-PaCa-2 cells exposed to H182 for 48 h showed a repression of genes involved in immune evasion (HLA-E, AGRN), angiogenesis (LOXL2), cell proliferation and migration (IL-8, UBC, JAG1), oxidative stress (NQO1, SRXN1, TXNRD1) and tumor progression (BCL10, HMOX1, HMGA1, SERPINE1), in parallel with the upregulation of TP53 and NBPF1 tumor suppressor genes. H182 treatment of the hPDAC lines further repressed mitochondrial oxygen consumption rate and viable cell numbers and induced apoptosis. Administration of H182 to HFD-fed KC mice prevented acinar cell differentiation into ADM/PanINs and suppressed pro-fibroinflammatory genes in the pancreas, including CXCL12, CCL2 and CCL5, while inhibiting the growth of subcutaneous hPDAC xenografts in mice. The decreased proinflammatory cytokine and chemokine profiles across diverse cell types, associated with the enrichment of acinar cells in the pancreas of KC mice in response to STAT3 inhibition underscores declining STAT3-dependent pro-tumorigenic mechanisms that are orchestrated through a HFD-induced chronic inflammation. The translational significance is that the blockade of aberrant STAT3 functions suppresses growth of PanINs and cancer cells in PDAC. Citation Format: Monday O. Ogese, Lihong Huo, Yue Chen, Benjamin Jackel, Francisco Lopez-Tapia, Richard T. Waldron, Aurelia Lugea, Stephen J. Pandol, James Turkson. STAT3 Orchestrates common and divergent mechanisms in different cell types to promote pancreatic cancer development and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1741.