PERSISTENCE OF SPLANCHNIC GENE SIGNATURE DEFINES A TUMOR-RESTRAINING FIBROBLAST SUBTYPE IN PANCREATIC CANCER

The pancreas is composed of the epithelial and mesenchymal cells. Interaction between the two lineages guides proper formation of the pancreas and modulates progression of pancreatic diseases such as cancer. While mesenchymal fibroblasts are a minor component of the normal pancreas, fibroblast population expands drastically during tumorigenesis. 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 cancer associated fibroblasts (CAFs). Single cell transcriptomic analysis further indicated persistent and dynamic gene expressions along the pancreatic mesenchymal trajectory during development, homeostasis and cancer (Nat Commun, 2023). Intriguingly, we found that two splanchnic transcription factors, FOXF1 and GATA6, 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. We constructed a dual DNA recombinase mouse genetic model, where DNA recombinase FlpO directs expression of an oncogene Kras (G12D mutation) and loss of a tumor suppressor p53 (two most frequent mutations in pancreatic cancer patients) in pancreatic epithelial cells, while DNA recombinase Cre deletes Gata6 specifically in CAFs. 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 suppress pancreatic cancer in a non-cell autonomous fashion. The enhancement of this mechanism could be explored further for therapeutic benefits.