Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion
- Queen Mary University of London, United Kingdom
- University College London, United Kingdom
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
Megan Daisy Joseph
Edward Philip Carter
Sabrina Simoncelli
Richard Philip Grose
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.
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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Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion
eLife 12:e86971.
https://doi.org/10.7554/eLife.86971
