SMAD4 and KRAS Status Shape Cancer Cell-Stromal Crosstalk and Therapeutic Response in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC. Here, we used single-cell RNA-sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V in which Smad4 was wild-type or deleted. KrasG12D Smad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared to KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy.