Abstract 3647: Oncogenic Kras drives cancer-associated fibroblast heterogeneity and substate changes in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is currently the third-leading cause of cancer-related deaths in the United States with no effective or targeted therapies to improve outcomes. Two defining features of PDAC are the dense stroma composing the bulk of the tumor mass and mutations in KRAS, the primary oncogene in most PDAC patients. Advances in knowledge on both fronts have led to promising avenues for therapeutics: recently described heterogeneity within the cancer-associated fibroblast (CAF) population residing in the stroma offers insight into the lack of success with therapies only targeting CAFs; and mutant KRAS inhibitors directed at the G12C isoform have received accelerated FDA approval for treatment of locally advanced and metastatic non-small cell lung cancer. However, the nature of this CAF heterogeneity is not yet fully understood, and any effects of KRAS blockade on the stroma have not been evaluated with consideration of this heterogeneity in mind. To assess how loss of Kras affects CAF heterogeneity and plasticity, we employed a genetically engineered mouse model (GEMM) of PDAC harboring a reversible oncogenic KrasG12V allele conditionally expressed from the endogenous Kras locus. This FPC compound mouse (KrasFrt-LSL-G12V-Frt; p53LSL-R172H; PDX-CRE; Rosa26FlpOERT2) spontaneously develops pancreatic lesions and allows for irreversible excision of the mutant Kras allele upon the application of Tamoxifen. Using single-cell RNA sequencing (scRNAseq), fluorescence in situ hybridization, and functional in vitro and in vivo approaches, we found that oncogenic Kras ablation led to tumor regression and altered cancer cell gene programs, profoundly affecting the tumor microenvironment, specifically CAF heterogeneity. Mutant Kras loss leads to decreased Tgfb1 expression in the cancer cells, but surprisingly also to increased Il1a levels, correlating with a reduction in myofibroblastic CAFs (myCAFs) and an expansion in inflammatory CAFs (iCAFs), respectively. Our results suggest that mutant Kras drives paracrine signaling that shapes CAF heterogeneity and should be considered for the development of the most effective therapeutic strategies. Citation Format: Jennifer S. Thalappillil, Giuseppina Caligiuri, Sandeep Nadella, Brinda Alagesan, Georgi N. Yordanov, Mojdeh Shakiba, Benjamin Kaminow, Juliene Hinds, Pedro A. Perez-Mancera, Jonathan Preall, Alexander Dobin, Youngkyu Park, David A. Tuveson. Oncogenic Kras drives cancer-associated fibroblast heterogeneity and substate changes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3647.