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NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast derived nutritional supply and immunosuppression

Ralph Francescone, Débora Barbosa Vendramini-Costa, Janusz Franco-Barraza, Jessica Wagner, Alexander Muir, Linara Gabitova, Tatiana Pazina, Tiffany Luong, Neelima Shah, Dustin Rollins, Ruchi Malik, Sapna Gupta, Roshan Thapa, Diana Restifo, Allison Lau, Yan Zhou, Kathy Q. Cai, Harvey Hensley, Emmanuelle Nicolas, Warren Kruger, Karthik Devarajan, Siddharth Balachandran, Wafik S. El-Deiry, Matthew Vander Heiden, Kerry S. Campbell, Igor Astsaturov, View ORCID ProfileEdna Cukierman
doi: https://doi.org/10.1101/330209
Ralph Francescone
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Débora Barbosa Vendramini-Costa
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Janusz Franco-Barraza
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Jessica Wagner
Molecular Therapeutics Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Alexander Muir
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge MA, 02139, USA
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Linara Gabitova
Molecular Therapeutics Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Tatiana Pazina
Blood Cell and Development and Function Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Tiffany Luong
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Neelima Shah
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Dustin Rollins
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Ruchi Malik
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Sapna Gupta
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Roshan Thapa
Blood Cell and Development and Function Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Diana Restifo
Molecular Therapeutics Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Allison Lau
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge MA, 02139, USA
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Yan Zhou
Molecular Therapeutics Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USABioinformatics and Bioinformatics Facility Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Kathy Q. Cai
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USAHistopatholgy Facility Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Harvey Hensley
Molecular Therapeutics Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USASmall Animal Imaging Facility Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Emmanuelle Nicolas
Genotyping and Real-Time PCR Facility Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Warren Kruger
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Karthik Devarajan
Bioinformatics and Bioinformatics Facility Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Siddharth Balachandran
Blood Cell and Development and Function Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Wafik S. El-Deiry
Molecular Therapeutics Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Matthew Vander Heiden
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge MA, 02139, USA
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Kerry S. Campbell
Blood Cell and Development and Function Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Igor Astsaturov
Molecular Therapeutics Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Edna Cukierman
Cancer Biology Program Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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  • ORCID record for Edna Cukierman
  • For correspondence: edna.cukierman@fccc.edu
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Summary

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of cancer-associated fibroblasts (CAFs) and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. Here, we uncovered the upregulation of NetrinG1 (NetG1) in CAFs and its binding partner NetrinG1 ligand (NGL-1) in PDAC cells and patient tissue samples. Using a three-dimensional culturing system, we observed that the NetG1/NGL-1 axis controls key pro-tumorigenic features of CAFs and PDAC cells, in cell autonomous and reciprocal manners. Results were confirmed in vivo using patient tissues and in a murine PDAC model in which NGL-1 ablation in PDAC cells significantly halted tumor growth. Thus, this study identifies two potential targets for PDAC, both tumoral and microenvironmental.

Significance PDAC has a 5-year survival rate of ~8% and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets and discern their functional roles. Using patient tissue and data, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified NetG1 and NGL-1 as major promoters of PDAC tumorigenesis. NetG1+ CAFs supported PDAC survival, through NetG1/NGL-1 mediated nutritional supply, dependent on glutamate metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of PDAC cells. NGL-1 controlled tumor cell fitness in vitro and in vivo, likely through metabolic communication with CAFs. Overall, we identified two putative targets in different cellular compartments in PDAC and disrupting solely one arm of the NetG1/NGL-1 axis significantly stunted tumorigenesis.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 19, 2018.
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NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast derived nutritional supply and immunosuppression
Ralph Francescone, Débora Barbosa Vendramini-Costa, Janusz Franco-Barraza, Jessica Wagner, Alexander Muir, Linara Gabitova, Tatiana Pazina, Tiffany Luong, Neelima Shah, Dustin Rollins, Ruchi Malik, Sapna Gupta, Roshan Thapa, Diana Restifo, Allison Lau, Yan Zhou, Kathy Q. Cai, Harvey Hensley, Emmanuelle Nicolas, Warren Kruger, Karthik Devarajan, Siddharth Balachandran, Wafik S. El-Deiry, Matthew Vander Heiden, Kerry S. Campbell, Igor Astsaturov, Edna Cukierman
bioRxiv 330209; doi: https://doi.org/10.1101/330209
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NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast derived nutritional supply and immunosuppression
Ralph Francescone, Débora Barbosa Vendramini-Costa, Janusz Franco-Barraza, Jessica Wagner, Alexander Muir, Linara Gabitova, Tatiana Pazina, Tiffany Luong, Neelima Shah, Dustin Rollins, Ruchi Malik, Sapna Gupta, Roshan Thapa, Diana Restifo, Allison Lau, Yan Zhou, Kathy Q. Cai, Harvey Hensley, Emmanuelle Nicolas, Warren Kruger, Karthik Devarajan, Siddharth Balachandran, Wafik S. El-Deiry, Matthew Vander Heiden, Kerry S. Campbell, Igor Astsaturov, Edna Cukierman
bioRxiv 330209; doi: https://doi.org/10.1101/330209

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