TY - JOUR
T1 - Oncogenic KRAS-driven metabolic reprogramming in pancreatic cancer cells utilizes cytokines from the tumor microenvironment
AU - Dey, Prasenjit
AU - Li, Jun
AU - Zhang, Jianhua
AU - Chaurasiya, Surendra
AU - Strom, Anders
AU - Wang, Huamin
AU - Liao, Wen Ting
AU - Cavallaro, Frederick
AU - Denz, Parker
AU - Bernard, Vincent
AU - Yen, Er Yen
AU - Genovese, Giannicola
AU - Gulhati, Pat
AU - Liu, Jielin
AU - Chakravarti, Deepavali
AU - Deng, Pingna
AU - Zhang, Tingxin
AU - Carbone, Federica
AU - Chang, Qing
AU - Ying, Haoqiang
AU - Shang, Xiaoying
AU - Spring, Denise J.
AU - Ghosh, Bidyut
AU - Putluri, Nagireddy
AU - Maitra, Anirban
AU - Wang, Y. Alan
AU - DePinho, Ronald A.
N1 - Funding Information:
The Metabolomic Core Facility at Baylor College of Medicine is supported by P30CA125123, CPRIT Proteomics and Metabolomics Core Facility (RP170005). In addition, this study was supported by NCI P01 CA117969 (to R.A. DePinho); NCI R01 CA225955 (to R.A. DePinho); DOD Postdoctoral Research Fellowship W81XWH-14-1-0429 (to P. Denz); K99/R00 grant 1K99 CA218891-01A1 (to P. Denz); U24 CA224020 (to A. Maitra); R01 CA218004 (to A. Maitra); R01 CA304969 (to A. Maitra). V. Bernard and D. Chakravarti were supported by the CPRIT Research Training Program (RP140106 and 170067). We thank Dr. Raghu Kalluri and colleagues for their critical review of the manuscript.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-19-0297
DO - 10.1158/2159-8290.CD-19-0297
M3 - Article
C2 - 32046984
AN - SCOPUS:85082779934
SN - 2159-8274
VL - 10
SP - 608
EP - 625
JO - Cancer discovery
JF - Cancer discovery
IS - 4
ER -