Abstract A045: Persistence of the splanchnic gene signature along the mesenchymal cell trajectory during pancreatic cancer progression

Abstract

Abstract In pancreatic ductal adenocarcinoma (PDAC), cancer associated fibroblasts (CAFs) play critical and complex roles in the tumor microenvironment. While fibroblasts are sparse in the normal adult pancreas, CAFs are a major component in the desmoplastic stroma of PDAC and may account for half of the entire tumor tissue. Here we aimed to investigate the origin, diversification, and function of CAFs. We constructed a dual-DNA-recombinase mouse genetic model, which allowed for genetic alternations in pancreatic epithelial cells and fibroblasts independently and simultaneously. The splanchnic mesenchyme is a layer of tissue adjacent to the pancreatic endoderm during fetal development. Our lineage tracing studies demonstrated that the splanchnic mesenchyme is the fetal origin of adult pancreatic fibroblasts during homeostasis and tumorigenesis. Notably, the other two postulated CAF sources, bone marrow and epithelial cells, have minimal contributions to fibroblasts. We further compared mice carrying no genetic mutations, only Kras mutation, and Kras/p53 dual mutations in pancreatic epithelial cells. We found that fibroblasts in all three conditions are derived from the splanchnic mesenchyme, suggesting a continuous mesenchymal trajectory in coordination with the pancreatic epithelium. Additionally, single cell transcriptomic analysis indicated persistent and dynamic gene expressions along the pancreatic mesenchymal trajectory during development, homeostasis, precancer lesion and cancer. Intriguingly, certain splanchnic factors are expressed in adult pancreatic fibroblasts in temporally and spatially distinct patterns. To determine the function of splanchnic factors in fibroblasts, we constructed mouse genetic models to delete GATA6 specifically in CAFs, which resulted in increased tumor burden in the pancreas. This suggests a non-cell autonomous function of GATA6 in CAFs to restrain pancreatic cancer progression. In summary, this study delineated a continuous cell trajectory of the mesenchymal lineage in the pancreas across different life stages. Furthermore, persistent gene expressions along the mesenchymal trajectory contributes to pancreatic CAF heterogeneity. Importantly, such persistence may constitute an inherent mechanism to restrain pancreatic cancer. Citation Format: Lu Han, Tom Walter, Joseph Beaudet, Caroline Everett, Julia Piermattei, Alex Adams, Kun Fang, Michael Zimmermann, Angela Mathison, Raul Urrutia, Victor Jin, Gustavo Leone, Michael Ostrowski. Persistence of the splanchnic gene signature along the mesenchymal cell trajectory during pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A045.