Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 13, Issue 6, Pages 1673-1699Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2022.02.016
Keywords
Pancreatic Cancer; Transformation; Fibroblasts; Macrophages
Categories
Funding
- National Institutes of Health/National Cancer Institute [R01CA151588, R01CA198074]
- University of Michigan Cancer Center Support Grant [NCI P30CA046592]
- American Cancer Society [RSG-16-005-01]
- National Cancer Institute [R37CA237421, R01CA248160, DK097153, P30CA046592, K08CA201581, S10OD28612-01-A1]
- Rackham Merit Fellowship
- Cellular Biotechnology Training Program
- Cancer Biology Training Program
- American Cancer Society Postdoctoral Award
- Michigan Institute for Clinical and Healthy Research Postdoctoral Translational Scholar Program fellowship award
- University of Michigan Training Program in Organogenesis (NIH)
- National Institutes of Health Cellular and Molecular Biology Training Grant
- Research Scholar Grant from the American Cancer Society
- Center for Organogenesis Training Program (National Institutes of Health)
- University of Michigan DNA Sequencing Core
- University of Michigan
- National Institutes of Health
- University of Michigan Comprehensive Cancer Center (UMCCC) Core Grant
- Association of Academic Surgery Joel Roslyn Award
- national institute of health grant
- Charles Woodson Research Fund
- University of Michigan (UM) Pediatric Brain Tumor Initiative
- Tissue and Molecular Pathology and Flow Cytometry Shared Resources at the Rogel Cancer Center
- CyTOF (Fluidigm, South San Francisco, CA)
- National Institutes of Health SIG
- [F31-CA247037]
- [R37CA214955]
- [F31-CA247076]
- [F31CA24745701]
- [T32GM008353]
- [T32-CA009676]
- [PF-19-096-01]
- [T32-HD007505]
- [T32-GM007315]
- [T32 HD007505]
- [T32-GM113900]
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This study reveals that non-cell autonomous oncogenic KRAS signaling can reprogram pancreatic fibroblasts, leading to an inflammatory response and affecting the tumor microenvironment, thereby promoting tumor development.
BACKGROUND & AIMS: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. METHODS: Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. RESULTS: We have discovered that non-cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. CONCLUSIONS: Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.
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