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

• DOI: 10.1158/0008-5472.c.7815494
• Publication Date: 2025-05-13T18:35:41Z
• Authors: Eloise G. Lloyd; Muntadher Jihad; Judhell S. Manansala; Wenlong Li; Priscilla S.W. Cheng; Gianluca Mucciolo; Marta Zaccaria; Sara Pinto Teles; Joaquín Araos Hen...; Sneha Harish; Rebecca Brais; Sally Ashworth; Weike Luo; Paul M. Johnson; Lisa Veghini; Mireia Vallespinos; Vincenzo Corbo; Giulia Biffi

<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing the dismal prognosis associated with this cancer. Evidence suggests PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on preclinical models driven <i>Kras</i><sup><i>G12D</i></sup> and mutant <i>Trp53</i>. Elucidation of contribution additional known oncogenic drivers, including <i>Kras</i><sup><i>G12V</i></sup> mutation <i>Smad4</i> loss, needed increase understanding cell–stromal cell cross-talk in PDAC. In study, we used single-cell RNA sequencing analyze cellular landscape <i>Trp53-</i>mutant mouse or <i>Kras</i><sup><i>G12V</i></sup>, which was wild type deleted. <i>Kras</i><sup><i>G12D</i></sup><i>Smad4</i>-deleted developed a fibro-inflammatory rich increased JAK/STAT signaling enhanced therapeutic inhibition. SMAD4 loss differently altered tumor microenvironment compared PDAC, compartment lacked dependency. Thus, genotype affects cancer phenotypes directly affecting efficacy.</p><p><b>Significance:</b> differentially impacts treatment sensitivity pancreatic tumors KRAS<sup>G12D</sup> KRAS<sup>G12V</sup>, highlighting importance genotype–phenotype relationships for precision therapy.</p></div>