KRAS mutation and epithelial-macrophage interplay in pancreatic neoplastic transformation

International Journal of Cancer. Journal International Du Cancer
Faraz BishehsariAli Keshavarzian

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased (i) ductal to acinar gene expression ratios, (ii) epithelial cells proliferation and (iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a protumorigenic phenotype in macrophages. Altered macrophages decreased epithelial pigment epithelial derived factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) and in our human PDA specimens. Epithelium-macrophage cross-talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a protumorigenic phenotype in macrophages, in turn augmenting neoplastic growth.

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Citations

Jun 27, 2019·Alcoholism, Clinical and Experimental Research·Faraz BishehsariAli Keshavarzian
Sep 5, 2020·Immunity, Inflammation and Disease·Andrea F CruzFarzad Esni
Jul 3, 2021·Biomedicines·Andrew ArmstrongFaraz Bishehsari
Jul 29, 2021·Cancer Cell International·Jia YaoXun Li
Oct 1, 2021·Cancer Metastasis Reviews·Cameron J HertingGregory B Lesinski

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