1. Cancer Biology
  2. Cell Biology

Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion

  1. Elena Tomas Bort
  2. Megan Daisy Joseph
  3. Qiaoying Wang
  4. Edward Philip Carter
  5. Nicolas Jaime Roth
  6. Jessica Gibson
  7. Ariana Samadi
  8. Hemant M Kocher
  9. Sabrina Simoncelli
  10. Peter J McCormick  Is a corresponding author
  11. Richard Philip Grose  Is a corresponding author
  1. Queen Mary University of London, United Kingdom
  2. University College London, United Kingdom
https://doi.org/10.7554/eLife.86971
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Cite this article
  1. Elena Tomas Bort
  2. Megan Daisy Joseph
  3. Qiaoying Wang
  4. Edward Philip Carter
  5. Nicolas Jaime Roth
  6. Jessica Gibson
  7. Ariana Samadi
  8. Hemant M Kocher
  9. Sabrina Simoncelli
  10. Peter J McCormick
  11. Richard Philip Grose
(2023)
Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion
eLife 12:e86971.
https://doi.org/10.7554/eLife.86971
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to show no improvement in survival rates. One aspect of PDAC is elevated ATP levels, pointing to the purinergic axis as a potential attractive therapeutic target. Mediated in part by highly druggable extracellular proteins, this axis plays essential roles in fibrosis, inflammation response and immune function. Analysing the main members of the PDAC extracellular purinome using publicly available databases discerned which members may impact patient survival. P2RY2 presents as the purinergic gene with the strongest association with hypoxia, the highest cancer cell-specific expression and the strongest impact on overall survival. Invasion assays using a 3D spheroid model revealed P2Y2 to be critical in facilitating invasion driven by extracellular ATP. Using genetic modification and pharmacological strategies we demonstrate mechanistically that this ATP-driven invasion requires direct protein-protein interactions between P2Y2 and αV integrins. DNA-PAINT super-resolution fluorescence microscopy reveals that P2Y2 regulates the amount and distribution of integrin αV in the plasma membrane. Moreover, receptor-integrin interactions were required for effective downstream signalling, leading to cancer cell invasion. This work elucidates a novel GPCR-integrin interaction in cancer invasion, highlighting its potential for therapeutic targeting.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file, or online resources are fully referenced.Human PDAC tumour data were generated by TCGA Research Network (https://www.cancer.gov/tcga) and by the Clinical Proteomic Tumour Analysis Consortium (https://www.proteomics.cancer.gov). The Genotype-Tissue Expression (GTEx) Project was used for the analysis of normal pancreatic tissue samples (https://gtexportal.org).

Article and author information

Author details

  1. Elena Tomas Bort

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7897-8891

  2. Megan Daisy Joseph

    London Centre for Nanotechnology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8313-8467

  3. Qiaoying Wang

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Edward Philip Carter

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4499-1101

  5. Nicolas Jaime Roth

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Jessica Gibson

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Ariana Samadi

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  8. Hemant M Kocher

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  9. Sabrina Simoncelli

    London Centre for Nanotechnology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7089-7667

  10. Peter J McCormick

    Centre for Endocrinology, Queen Mary University of London, London, United Kingdom
    For correspondence
    p.mccormick@qmul.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2225-5181

  11. Richard Philip Grose

    Centre for Tumour Biology, Queen Mary University of London, London, United Kingdom
    For correspondence
    r.p.grose@qmul.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4738-0173

Funding

Cancer Research UK (A27781)

  • Edward Philip Carter

Cancer Research UK (A25137)

  • Edward Philip Carter
  • Richard Philip Grose

Medical Research Council (MRC0227)

  • Elena Tomas Bort

Biotechnology and Biological Sciences Research Council (BB/T008709/1)

  • Megan Daisy Joseph

Royal Society (DHF\R1\191019)

  • Sabrina Simoncelli

Royal Society (RGS\R2\202038)

  • Sabrina Simoncelli

Medical Research Council (MR/N014308/1)

  • Nicolas Jaime Roth

Pancreatic Cancer Research Fund (Tissue Bank Grant)

  • Hemant M Kocher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Version history

  1. Preprint posted: October 24, 2022 (view preprint)
  2. Received: February 14, 2023
  3. Accepted: March 17, 2023
  4. Accepted Manuscript published: March 21, 2023 (version 1)
  5. Version of Record published: April 3, 2023 (version 2)

Copyright

© 2023, Tomas Bort et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Elena Tomas Bort
  2. Megan Daisy Joseph
  3. Qiaoying Wang
  4. Edward Philip Carter
  5. Nicolas Jaime Roth
  6. Jessica Gibson
  7. Ariana Samadi
  8. Hemant M Kocher
  9. Sabrina Simoncelli
  10. Peter J McCormick
  11. Richard Philip Grose
(2023)
Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion
eLife 12:e86971.
https://doi.org/10.7554/eLife.86971

Share this article

https://doi.org/10.7554/eLife.86971

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