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Francescone R , Barbosa Vendramini-Costa D , Franco-Barraza J , Wagner J , Muir A , Lau AN , Gabitova L , Pazina T , Gupta S , Luong T , Rollins D , Malik R , Thapa RJ , Restifo D , Zhou Y , Cai KQ , Hensley HH , Tan Y , Kruger WD , Devarajan K , Balachandran S , Klein-Szanto AJ , Wang H , El-Deiry WS , Vander Heiden MG , Peri S , Campbell KS , Astsaturov I , Cukierman E
Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression
Cancer Discov. 2021 Feb;11(2) :446-479
PMID: 33127842    PMCID: PMC7858242    URL: https://www.ncbi.nlm.nih.gov/pubmed/33127842
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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 multi-plex data from patient tissue, three-dimensional co-culturing 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 (CAFs) support PDAC survival, through a NetG1 mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit NK cell mediated killing of tumor cells. These pro-tumor functions are controlled by a signaling circuit downstream to 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.
Notes
2159-8290 Francescone, Ralph Barbosa Vendramini-Costa, Débora Orcid: 0000-0001-7617-4945 Franco-Barraza, Janusz Orcid: 0000-0003-3652-5311 Wagner, Jessica Muir, Alexander Lau, Allison N Gabitova, Linara Pazina, Tatiana Gupta, Sapna Luong, Tiffany Rollins, Dustin Malik, Ruchi Thapa, Roshan J Restifo, Diana Zhou, Yan Cai, Kathy Q Hensley, Harvey H Tan, Yinfei Kruger, Warren D Orcid: 0000-0002-4990-3695 Devarajan, Karthik Balachandran, Siddharth Klein-Szanto, Andres J Wang, Huamin El-Deiry, Wafik S Vander Heiden, Matthew G Orcid: 0000-0002-6702-4192 Peri, Suraj Campbell, Kerry S Orcid: 0000-0003-4665-7326 Astsaturov, Igor Cukierman, Edna R01 CA188430/CA/NCI NIH HHS/ R01 CA232256/CA/NCI NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ Cancer Discov. 2021 Feb;11(2):446-479. doi: 10.1158/2159-8290.CD-20-0775. Epub 2020 Oct 30.