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

Abstract

ABSTRACTPancreatic 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 byKrasG12Dand mutantTrp53and have not assessed the contribution of other known oncogenic drivers, includingKRASG12Vand alterations inCDKN2AandSMAD4. To increase understanding of malignant cell-stroma crosstalk in PDAC, we analyzedTrp53-mutant mouse models driven byKrasG12DorKrasG12Vin whichSmad4was 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 ofSmad4-deletedKrasG12VPDAC 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.STATEMENT OF SIGNIFICANCEUnderstanding malignant cell-stroma crosstalk in PDAC has focused on models containingKrasG12Dand mutantTrp53. Here, we show that PDAC driven byKrasG12DorKrasG12Vin whichSmad4is deleted display differences in malignant-stromal signaling and treatment sensitivity, highlighting the importance of understanding genotype-phenotype relationships for precision PDAC therapy.