Abstract IA19: Oncogenic KRAS and the regulation of the pancreatic cancer microenvironment.

Abstract Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is characterized by almost universal presence of oncogenic KRAS. A key characteristic of pancreatic cancer is the abundant accumulation of tumor microenvironment, rich in infiltrating immune cells and an extensive fibroblast population. Pancreatic cancer is preceded by precursor lesions known as Pancreatic Intraepithelial Neoplasia (PanIN); PanIN formation is accompanied by the formation of a pre-TME. Analysis of donor pancreas from healthy individual revealed that PanIN is common in human samples, and accompanied by pre-TME accumulation in human samples. We sought to determine whether oncogenic KRAS drives accumulation and maintenance of the pre-TME. For this purpose, we utilized the iKRAS mouse model of pancreatic cancer, which allows tissue-specific, inducible and reversible activation of KRASG12D, the most common mutant form in human pancreatic cancer. Activation of oncogenic KRAS in iKRAS mice leads to PanIN formation. We observed that fibroblast activation occurs upon KRAS activation and precedes the formation of overt lesions. Further, epithelial oncogenic KRAS is required to maintain fibroblast reprogramming in PanIN. To comprehensively understand changes in fibroblasts, we used single cell RNA sequencing, and observed that the fibroblast transcriptional program is extrinsically regulated by epithelial oncogenic KRAS. The reprogramming process can be modeled in vivo using conditioned media from pancreatic cancer cells expressing oncogenic KRAS, and is mediated by JAK/STAT3 signaling in fibroblasts. We then sought to determine whether the extrinsic effects of oncogenic KRAS induced reprogramming of fibroblasts at distal sites. We chose to study the lung, which is a common site of metastasis for pancreatic cancer. Our data show that lung fibroblasts are activated following expression of oncogenic KRAS in the pancreas; fibroblast activation is accompanied by phospho-Stat3 signaling, a readout of the JAK/Stat3 pathway, and precedes metastasis outgrowth in the pancreas. Thus, oncogenic KRAS extrinsically reprograms the local and systemic environments, possibly facilitating metastatic spread of pancreatic cancer. Citation Format: Marina Pasca di Magliano. Oncogenic KRAS and the regulation of the pancreatic cancer microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA19.