1. Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression
- Author
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Kathy Q. Cai, Kerry S. Campbell, Tiffany Luong, Tatiana Pazina, Wafik S. El-Deiry, Allison N. Lau, Ruchi Malik, Débora Barbosa Vendramini-Costa, Harvey Hensley, Alexander Muir, Dustin Rollins, Ralph Francescone, Yan Zhou, Siddharth Balachandran, Edna Cukierman, Sapna Gupta, Karthik Devarajan, Warren D. Kruger, Huamin Wang, Roshan J. Thapa, Matthew G. Vander Heiden, Jessica Wagner, Yinfei Tan, Diana Restifo, Andres J. Klein-Szanto, Suraj Peri, Igor Astsaturov, Linara Gabitova, and Janusz Franco-Barraza
- Subjects
0301 basic medicine ,p38 mitogen-activated protein kinases ,Vesicular glutamate transporter 1 ,Adenocarcinoma ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Glutamine synthetase ,Netrin ,Tumor Microenvironment ,medicine ,Humans ,Neutralizing antibody ,Protein kinase B ,Immunosuppression Therapy ,Nutritional Support ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Netrins ,Carcinogenesis ,Carcinoma, Pancreatic Ductal - 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 immunosuppressive 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 neutralizing 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. See related commentary by Sherman, p. 230. This article is highlighted in the In This Issue feature, p. 211
- Published
- 2021
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