Abstract B015: Systemic reprogramming of fibroblasts and immune cells precedes metastatic spread in pancreatic cancer

Abstract

Abstract Oncogenic KRAS (Kras*) is a near-universal driver of pancreatic ductal adenocarcinoma (PDA), and its activity is required for the formation of the PDA precursor lesions, pancreatic intraepithelial neoplasia (PanIN). PanIN formation is accompanied by fibrosis and immune cell infiltration, creating a precursor tumor microenvironment (PME) that is maintained and evolves through the disease progression. In mice bearing overt pancreatic cancer, pancreatic cells secrete specific factors to prime the liver and lung, forming the premetastatic niche. Presently, it remains to be elucidated at what stage of PDA tumorigenesis the premetastatic niche is initiated, as well as the mechanisms underlying this formation. As PDA patients are commonly diagnosed with metastatic disease, it is imperative to understand the mechanism underlying formation of the premetastatic niche, as well as determinants of metastasis outgrowth. To determine whether Kras*-dependent signals are required for the formation of the premetastatic niche, we used an inducible and reversible murine model of pancreas-specific Kras* expression developed by our group known as the iKras* mouse. We expressed Kras* in the pancreatic epithelium of adult mice for 16 weeks and validated the presence of advanced PanIN lesions without overt malignancy. We then performed single cell RNA sequencing (scRNA-seq) on the pancreas, liver, and lung of these mice, with liver and lung being common sites of metastasis for pancreatic cancer. We have previously shown that pancreatic fibroblasts are reprogrammed early during carcinogenesis, a finding that holds true at this later timepoint. Interestingly, we observed parallel changes in gene expression in fibroblasts, macrophages, and T cells in the lungs of PanIN bearing mice. Ongoing studies aim to validate the changes seen in the scRNA-seq and functionally evaluate systemic activation of fibroblasts and immune cells within the premetastatic niche. Citation Format: Emily L. Lasse Opsahl, Ashley Velez-Delgado, Katelyn L. Donahue, Padma Kadiyala, Carlos Espinoza, Yaqing Zhang, Marina Pasca di Magliano. Systemic reprogramming of fibroblasts and immune cells precedes metastatic spread in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B015.