KRAS mutation and epithelial–macrophage interplay in pancreatic neoplastic transformation

• Published in: International journal of cancer 2018-10, Vol.143 (8), p.1994-2007
• Main Authors: Bishehsari, Faraz, Zhang, Lijuan, Barlass, Usman, Preite, Nailliw Z., Turturro, Sanja, Najor, Matthew S., Shetuni, Brandon B., Zayas, Janet P., Mahdavinia, Mahboobeh, Abukhdeir, Abde M., Keshavarzian, Ali
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; Cancer; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Female; Gene expression; Genetic transformation; Genomes; Genotype & phenotype; Humans; K-Ras protein; KRAS; macrophage; Macrophages; Macrophages - metabolism; Macrophages - pathology; Medical research; Metastases; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Mutation - genetics; Organoids; Pancreas; Pancreas - metabolism; Pancreas - pathology; pancreas cancer; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; PEDF; Phenotypes; Precancerous Conditions - genetics; Precancerous Conditions - pathology; Proto-Oncogene Proteins p21(ras) - genetics; RAW 264.7 Cells; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31592

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. What's new? Pancreatic ductal adenocarcinoma is characterized by mutations in the proto‐oncogene KRAS and proinflammatory macrophage infiltration, but a mechanistic link between both conditions remains unknown. Here the authors used murine pancreatic organoid models to demonstrate cooperativity between epithelial cells carrying mutant KRAS and invading macrophages in pancreatic neoplastic transformation. These results encourage more research into the bidirectional epithelium–macrophage cross‐talk as it could reveal novel targets for pancreatic cancer therapy.