2. Academic Validation
  3. Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth

Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth

  • Nat Cancer. 2022 Aug;3(8):945-960. doi: 10.1038/s43018-022-00426-6.
Meng Yuan  # 1 2,  Bo Tu  # 3 4,  Hengchao Li  # 5,  Huanhuan Pang  # 6,  Nan Zhang 1,  Minghe Fan 1,  Jingru Bai 1,  Wei Wang 7,  Zhaoqi Shu 1,  Christopher C DuFort 4,  Sihan Huo 1,  Jie Zhai 1,  Ke Yao 5,  Lina Wang 1,  Haoqiang Ying 3,  Wei-Guo Zhu 2 8,  Deliang Fu 9,  Zeping Hu 10,  Ying Zhao 11
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 2 Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, China.
  • 3 Molecular and Cellular Oncology Department, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 5 Department of Pancreatic Surgery, Huashan hospital, Institute of Pancreatic Disease, FuDan University, Shanghai, China.
  • 6 School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China.
  • 7 Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology, Beijing, China.
  • 8 Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, China.
  • 9 Department of Pancreatic Surgery, Huashan hospital, Institute of Pancreatic Disease, FuDan University, Shanghai, China. surgeonfu@163.com.
  • 10 School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China. zeping_hu@mail.tsinghua.edu.cn.
  • 11 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. zhaoying0812@bjmu.edu.cn.
  • # Contributed equally.
PMID: 35982178 DOI: 10.1038/s43018-022-00426-6
Abstract

Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through Autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.

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