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

Abstract:

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 the stromal composition of PDAC is shaped by mutations within malignant cells; however, most pre-clinical models of PDAC are driven by Kras G12D and mutant Trp53 and have not assessed the contribution of other known oncogenic drivers, including KRAS G12V and alterations in CDKN2A and SMAD4 . To increase understanding of malignant cell-stroma crosstalk in PDAC, we analyzed Trp53- mutant mouse models driven by Kras G12D or Kras G12V in which Smad4 was wild-type or deleted. Kras G12D ; 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 Kras G12V 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. STATEMENT OF SIGNIFICANCE Understanding malignant cell-stroma crosstalk in PDAC has focused on models containing Kras G12D and mutant Trp53 . Here, we show that PDAC driven by Kras G12D or Kras G12V in which Smad4 is deleted display differences in malignant-stromal signaling and treatment sensitivity, highlighting the importance of understanding genotype-phenotype relationships for precision PDAC therapy.

Authors:

EG Lloyd, M Jihad, JS Manansala, W Li, PSW Cheng, SP Teles, G Mucciolo, JA Henríquez, S Ashworth, W Luo, S Harish, PM Johnson, L Veghini, M Zaccaria, R Brais, M Vallespinos, V Corbo, G Biffi

Publication date:

2nd May 2024

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