Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment
Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ–IL4rα and IL2rγ–IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ–IL4rα and IL2rγ–IL13rα1 receptors signal primarily via JAK1–STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-0297
Entities
People
- Anders Strom
- Anirban Maitra
- Bidyut Ghosh
- Deepavali Chakravarti
- Denise J Spring
- Er-Yen Yen
- Federica Carbone
- Frederick Cavallaro
- Giannicola Genovese
- Haoqiang Ying
- Huamin Wang
- Jianhua Zhang
- Jielin Liu
- Jun Li
- Nagireddy Putluri
- Parker Denz
- Pat Gulhati
- Pingna Deng
- Prasenjit Dey
- Qing Chang
- Ronald A. DePinho
- Surendra Chaurasiya
- Tingxin Zhang
- Vincent Bernard
- Wen-Ting Liao
- Xiaoying Shang
- Yanru Wang
Organizations
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- Roswell Park Comprehensive Cancer Center
- The University of Texas MD Anderson Cancer Center
- United States Department of Defense
- University of Houston
- University of Texas at Austin