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

Meng Yuan, Bo Tu, Hengchao Li, Huanhuan Pang, Nan Zhang, Minghe Fan, Jingru Bai, Wei Wang, Zhaoqi Shu, Christopher C. DuFort, Sihan Huo, Jie Zhai, Ke Yao, Lina Wang, Haoqiang Ying, Wei Guo Zhu, Deliang Fu, Zeping Hu, Ying Zhao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)945-960
Number of pages16
JournalNature Cancer
Volume3
Issue number8
DOIs
StatePublished - Aug 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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