Data from SMAD4 and KRAS Status Shapes Cancer Cell–Stromal Cross-Talk and Therapeutic Response in Pancreatic Cancer

<div>Abstract<p>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 preclinical models driven by <i>Kras</i>^<i>G12D</i> and mutant <i>Trp53</i>. Elucidation of the contribution of additional known oncogenic drivers, including <i>Kras</i>^<i>G12V</i> mutation and <i>Smad4</i> loss, is needed to increase the understanding of malignant cell–stromal cell cross-talk in PDAC. In this study, we used single-cell RNA sequencing to analyze the cellular landscape of <i>Trp53-</i>mutant mouse models driven by <i>Kras</i>^<i>G12D</i> or <i>Kras</i>^<i>G12V</i>, in which <i>Smad4</i> was wild type or deleted. <i>Kras</i>^<i>G12D</i><i>Smad4</i>-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 <i>Kras</i>^<i>G12V</i> PDAC differently altered the tumor microenvironment compared with <i>Kras</i>^<i>G12D</i> PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype affects cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy.</p><p><b>Significance:</b> SMAD4 loss differentially impacts malignant cell–stromal cell signaling and treatment sensitivity of pancreatic tumors driven by KRAS^G12D or KRAS^G12V, highlighting the importance of understanding genotype–phenotype relationships for precision therapy.</p></div>