Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression
© 2020 American Association for Cancer Research. 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 vitr...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for Cancer Research (AACR)
2022
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| Online Access: | https://hdl.handle.net/1721.1/136086.2 |
| _version_ | 1811076387731144704 |
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| author | Francescone, Ralph Barbosa Vendramini-Costa, Débora Franco-Barraza, Janusz 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. Devarajan, Karthik Balachandran, Siddharth Klein-Szanto, Andres J. Wang, Huamin El-Deiry, Wafik S. Vander Heiden, Matthew G. Peri, Suraj Campbell, Kerry S. Astsaturov, Igor Cukierman, Edna |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Francescone, Ralph Barbosa Vendramini-Costa, Débora Franco-Barraza, Janusz 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. Devarajan, Karthik Balachandran, Siddharth Klein-Szanto, Andres J. Wang, Huamin El-Deiry, Wafik S. Vander Heiden, Matthew G. Peri, Suraj Campbell, Kerry S. Astsaturov, Igor Cukierman, Edna |
| author_sort | Francescone, Ralph |
| collection | MIT |
| description | © 2020 American Association for Cancer Research. 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. |
| first_indexed | 2024-09-23T10:20:39Z |
| format | Article |
| id | mit-1721.1/136086.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:20:39Z |
| publishDate | 2022 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/136086.22024-06-07T17:48:37Z Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression Francescone, Ralph Barbosa Vendramini-Costa, Débora Franco-Barraza, Janusz 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. Devarajan, Karthik Balachandran, Siddharth Klein-Szanto, Andres J. Wang, Huamin El-Deiry, Wafik S. Vander Heiden, Matthew G. Peri, Suraj Campbell, Kerry S. Astsaturov, Igor Cukierman, Edna Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Biology © 2020 American Association for Cancer Research. 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. 2022-02-10T22:55:04Z 2021-10-27T20:30:44Z 2022-02-10T22:55:04Z 2020-10 2020-09 2021-08-03T16:48:29Z Article http://purl.org/eprint/type/JournalArticle 2159-8274 2159-8290 https://hdl.handle.net/1721.1/136086.2 en http://dx.doi.org/10.1158/2159-8290.cd-20-0775 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/octet-stream American Association for Cancer Research (AACR) PMC |
| spellingShingle | Francescone, Ralph Barbosa Vendramini-Costa, Débora Franco-Barraza, Janusz 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. Devarajan, Karthik Balachandran, Siddharth Klein-Szanto, Andres J. Wang, Huamin El-Deiry, Wafik S. Vander Heiden, Matthew G. Peri, Suraj Campbell, Kerry S. Astsaturov, Igor Cukierman, Edna Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression |
| title | Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression |
| title_full | Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression |
| title_fullStr | Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression |
| title_full_unstemmed | Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression |
| title_short | Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression |
| title_sort | netrin g1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression |
| url | https://hdl.handle.net/1721.1/136086.2 |
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