Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast–driven nutritional support and immunosuppression

Ralph Francescone, Débora Barbosa Vendramini-Costa, Janusz Franco-Barraza, Jessica Wagner, Alexander Muir, Allison N. Lau, Linara Gabitova, Tatiana Pazina, Sapna Gupta, Tiffany Luong, Dustin Rollins, Ruchi Malik, Roshan J. Thapa, Diana Restifo, Yan Zhou, Kathy Q. Cai, Harvey H. Hensley, Yinfei Tan, Warren D. Kruger, Karthik DevarajanSiddharth Balachandran, Andres J. Klein-Szanto, Huamin Wang, Wafik S. El-Deiry, Matthew G. Vander Heiden, Suraj Peri, Kerry S. Campbell, Igor Astsaturov, Edna Cukierman

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosup-pressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutral-izing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.

Original languageEnglish
Pages (from-to)446-479
Number of pages34
JournalCancer Discovery
Volume11
Issue number2
DOIs
StatePublished - 2021

Keywords

  • Adenocarcinoma/metabolism
  • Carcinoma, Pancreatic Ductal/metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunosuppression Therapy
  • Netrins/metabolism
  • Nutritional Support
  • Pancreatic Neoplasms/metabolism
  • Tumor Microenvironment

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