Oncogenic KRAS-driven metabolic reprogramming in pancreatic cancer cells utilizes cytokines from the tumor microenvironment

Prasenjit Dey, Jun Li, Jianhua Zhang, Surendra Chaurasiya, Anders Strom, Huamin Wang, Wen Ting Liao, Frederick Cavallaro, Parker Denz, Vincent Bernard, Er Yen Yen, Giannicola Genovese, Pat Gulhati, Jielin Liu, Deepavali Chakravarti, Pingna Deng, Tingxin Zhang, Federica Carbone, Qing Chang, Haoqiang YingXiaoying Shang, Denise J. Spring, Bidyut Ghosh, Nagireddy Putluri, Anirban Maitra, Y. Alan Wang, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 (IL2r γ -IL4r α and IL2r γ -IL13r α 1) 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 IL2r γ -IL4r α and IL2r γ -IL13r α 1 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. SIGNIFICANCE: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.

Original languageEnglish (US)
Pages (from-to)608-625
Number of pages18
JournalCancer Discovery
Volume10
Issue number4
DOIs
StatePublished - Apr 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology

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