Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression

被引：132

作者：

Francescone, Ralph ^{[1
,2
]}

Vendramini-Costa, Debora Barbosa ^{[1
,2
]}

Franco-Barraza, Janusz ^{[1
,2
]}

Wagner, Jessica ^{[3
]}

Muir, Alexander ^{[4
,5
,6
]}

Lau, Allison N. ^{[4
,5
]}

Gabitova, Linara ^{[2
,3
]}

Pazina, Tatiana ^{[7
]}

Gupta, Sapna ^{[1
]}

Luong, Tiffany ^{[1
,2
]}

Rollins, Dustin ^{[1
]}

Malik, Ruchi ^{[1
,2
]}

Thapa, Roshan J. ^{[7
]}

Restifo, Diana ^{[2
,3
]}

Zhou, Yan ^{[3
,8
]}

Cai, Kathy Q. ^{[1
,9
]}

Hensley, Harvey H. ^{[3
,10
]}

Tan, Yinfei ^{[1
,11
]}

Kruger, Warren D. ^{[1
]}

Devarajan, Karthik ^{[8
]}

Balachandran, Siddharth ^{[7
]}

Klein-Szanto, Andres J. ^{[1
,9
]}

Wang, Huamin ^{[12
]}

El-Deiry, Wafik S. ^{[3
,13
]}

Vander Heiden, Matthew G. ^{[4
,5
,14
]}

Peri, Suraj ^{[8
]}

Campbell, Kerry S. ^{[2
,7
]}

Astsaturov, Igor ^{[2
,3
]}

Cukierman, Edna ^{[1
,2
]}

机构：

[1] Fox Chase Canc Ctr, Inst Canc Res, Canc Biol Program, Philadelphia, PA 19111 USA

[2] Fox Chase Canc Ctr, Marvin & Concetta Greenberg Pancreat Canc Inst, Inst Canc Res, Philadelphia, PA 19111 USA

[3] Fox Chase Canc Ctr, Inst Canc Res, Mol Therapeut Program, Philadelphia, PA 19111 USA

[4] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[5] MIT, Dept Biol, Cambridge, MA USA

[6] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA

[7] Fox Chase Canc Ctr, Inst Canc Res, Blood Cell & Dev & Funct Program, Philadelphia, PA 19111 USA

[8] Fox Chase Canc Ctr, Inst Canc Res, Biostat & Bioinformat Facil, Philadelphia, PA 19111 USA

[9] Fox Chase Canc Ctr, Inst Canc Res, Histopathol Facil, Philadelphia, PA 19111 USA

[10] Fox Chase Canc Ctr, Inst Canc Res, Small Anim Imaging Facil, Philadelphia, PA 19111 USA

[11] Fox Chase Canc Ctr, Inst Canc Res, Genom Facil, Philadelphia, PA 19111 USA

[12] Univ Texas MD Anderson Canc Ctr, Div Pathol Lab Med, Dept Anat Pathol, Houston, TX 77030 USA

[13] Brown Univ, Dept Pathol & Lab Med, Warren Alpert Med Sch, Providence, RI 02912 USA

[14] Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

CANCER DISCOVERY | 2021年 / 11卷 / 02期

关键词：

STELLATE CELLS; TUMOR METABOLISM; EXPRESSION; CARCINOMA; MICROENVIRONMENT; PATHWAY; STRESS; GROWTH; PLAYS; MACROPINOCYTOSIS;

D O I：

10.1158/2159-8290.CD-20-0775

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：446 / 479

页数：34

共 132 条

[1] p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis [J].

Alspach, Elise ;

Flanagan, Kevin C. ;

Luo, Xianmin ;

Ruhland, Megan K. ;

Huang, Hui ;

Pazolli, Ermira ;

Donlin, Maureen J. ;

Marsh, Timothy ;

Piwnica-Worms, David ;

Monahan, Joseph ;

Novack, Deborah V. ;

McAllister, Sandra S. ;

Stewart, Sheila A. .

CANCER DISCOVERY, 2014, 4 (06) :716-729

[2] Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts [J].

Amatangelo, MD ;

Bassi, DE ;

Klein-Szanto, AJP ;

Cukierman, E .

AMERICAN JOURNAL OF PATHOLOGY, 2005, 167 (02) :475-488

[3] HTSeq-a Python']Python framework to work with high-throughput sequencing data [J].

Anders, Simon ;

Pyl, Paul Theodor ;

Huber, Wolfgang .

BIOINFORMATICS, 2015, 31 (02) :166-169

[4]

Andrew AS, 2017, INT J MOL SCI, V18, DOI [10.3390/ijms18030535, 10.3390/ijms18030651]

[5]

[Anonymous], AACRJOURNALS ORG

[6] AP-1 Transcription Factors as Regulators of Immune Responses in Cancer [J].

Atsaves, Vasileios ;

Leventaki, Vasiliki ;

Rassidakis, George Z. ;

Claret, Francois X. .

CANCERS, 2019, 11 (07)

[7] Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer [J].

Bayne, Lauren J. ;

Beatty, Gregory L. ;

Jhala, Nirag ;

Clark, Carolyn E. ;

Rhim, Andrew D. ;

Stanger, Ben Z. ;

Vonderheide, Robert H. .

CANCER CELL, 2012, 21 (06) :822-835

[8] Screening of Conditionally Reprogrammed Patient-Derived Carcinoma Cells Identifies ERCC3-MYC Interactions as a Target in Pancreatic Cancer [J].

Beglyarova, Natalya ;

Banina, Eugenia ;

Zhou, Yan ;

Mukhamadeeva, Ramilia ;

Andrianov, Grigorii ;

Bobrov, Egor ;

Lysenko, Elena ;

Skobeleva, Natalya ;

Gabitova, Linara ;

Restifo, Diana ;

Pressman, Max ;

Serebriiskii, Ilya G. ;

Hoffman, John P. ;

Paz, Keren ;

Behrens, Diana ;

Khazak, Vladimir ;

Jablonski, Sandra A. ;

Golemis, Erica A. ;

Weiner, Louis M. ;

Astsaturov, Igor .

CLINICAL CANCER RESEARCH, 2016, 22 (24) :6153-6163

[9] Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts [J].

Bhagat, Tushar D. ;

Von Ahrens, Dagny ;

Dawlaty, Meelad ;

Zou, Yiyu ;

Baddour, Joelle ;

Achreja, Abhinav ;

Zhao, Hongyun ;

Yang, Lifeng ;

Patel, Brijesh ;

Kwak, Changsoo ;

Choudhary, Gaurav S. ;

Gordon-Mitchell, Shanisha ;

Aluri, Srinivas ;

Bhattacharyya, Sanchari ;

Sahu, Srabani ;

Bhagat, Prafulla ;

Yu, Yiting ;

Bartenstein, Matthias ;

Giricz, Orsi ;

Suzuki, Masako ;

Sohal, Davendra ;

Gupta, Sonal ;

Guerrero, Paola A. ;

Batra, Surinder ;

Goggins, Michael ;

Steidl, Ulrich ;

Greally, John ;

Agarwal, Beamon ;

Pradhan, Kith ;

Banerjee, Debabrata ;

Nagrath, Deepak ;

Maitra, Anirban ;

Verma, Amit .

ELIFE, 2019, 8

[10] Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism [J].

Biancur, Douglas E. ;

Paulo, Joao A. ;

Malachowska, Beata ;

Del Rey, Maria Quiles ;

Sousa, Cristovao M. ;

Wang, Xiaoxu ;

Sohn, Albert S. W. ;

Chu, Gerald C. ;

Gygi, Steven P. ;

Harper, J. Wade ;

Fendler, Wojciech ;

Mancias, Joseph D. ;

Kimmelman, Alec C. .

NATURE COMMUNICATIONS, 2017, 8

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