Abstract A044: Persistence of fetal splanchnic gene signature defines a tumor-restraining fibroblast subtype in pancreatic cancer

Abstract The pancreas is composed of the epithelial and mesenchymal cells. While mesenchymal fibroblasts are a minor component of the normal pancreas, fibroblast population expands drastically during tumorigenesis. In pancreatic ductal adenocarcinoma (PDAC), cancer associated fibroblasts (CAFs) play critical and complex roles in the tumor microenvironment. This study sought to define the origin, heterogeneity and function of pancreatic cancer associated fibroblasts. Recently we performed a series of lineage tracing studies in genetically engineered mouse models. This identified the splanchnic mesenchyme (a tissue layer adjacent to the developing fetal pancreatic epithelium) as the fetal origin of the adult pancreatic resident fibroblasts and pancreatic CAFs. Single cell transcriptomic analysis indicated persistent and dynamic gene expressions along the pancreatic mesenchymal trajectory during development, homeostasis, precancer and cancer. Intriguingly, we found that two splanchnic transcription factors, GATA6 and FOXF1, are expressed in only subsets of adult pancreatic fibroblasts in temporally and spatially distinct patterns. Similar patterns were observed in both mouse models and human patient samples. To determine the role of GATA6 in fibroblasts during tumorigenesis, we constructed a dual DNA recombinase mouse genetic model. DNA recombinase FlpO directs expression of an oncogene Kras (G12D mutation) and loss of a tumor suppressor p53 in pancreatic epithelial cells to induce spontaneous tumor formation in the pancreas, and DNA recombinase Cre deletes Gata6 specifically in fibroblasts. This fibroblast specific Gata6 deletion resulted in altered number and gene expression of CAFs as well as increased tumor burden in the pancreas. This suggests a non-cell autonomous function of GATA6 within 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. Additionally, this study provides evidence that persistent and selective gene expressions along the mesenchymal trajectory contributes to pancreatic CAF heterogeneity and such persistence may constitute an inherent host defense mechanism to restrain pancreatic cancer. The enhancement of this mechanism could be explored further for therapeutic benefits. Citation Format: Lu Han, Tom Walter, Joseph Beaudet, Caroline Everett, Gustavo Leone, Michael Ostrowski. Persistence of fetal splanchnic gene signature defines a tumor-restraining fibroblast subtype in pancreatic cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr A044.