SMAD4 and KRAS status shape malignant-stromal crosstalk in pancreatic cancer

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 the stromal composition of PDAC is shaped by mutations within malignant cells; however, most pre-clinical models of PDAC are driven by KrasG12D and mutant Trp53 and have not assessed the contribution of other known oncogenic drivers, including KRASG12V and alterations in CDKN2A and SMAD4. To increase understanding of malignant cell-stroma crosstalk in PDAC, we analyzed 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 JAK/STAT malignant cell signaling and an enhanced therapeutic response to JAK/STAT inhibition. In stark contrast, the stroma of Smad4-deleted KrasG12V PDAC was differently altered, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts malignant-stromal phenotype in PDAC, directly affecting therapeutic efficacy.