Bort, ET;
Joseph, MD;
Wang, Q;
Carter, EP;
Roth, NJ;
Gibson, J;
Samadi, A;
... Grose, RP; + view all
(2023)
Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion.
eLife
, 12
, Article e86971. 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. Analyzing 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 signaling, leading to cancer cell invasion. This work elucidates a novel GPCR-integrin interaction in cancer invasion, highlighting its potential for therapeutic targeting.
| Type: | Article |
|---|---|
| Title: | Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.7554/elife.86971 |
| Publisher version: | https://doi.org/10.7554/elife.86971 |
| Language: | English |
| Additional information: | © Copyright Tomas Bort et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. |
| Keywords: | 3D modelling, DNA-PAINT, cancer biology, cell biology, human, invasion, pancreatic cancer, purinergic signalling, Humans, Cell Line, Tumor, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Neoplasm Invasiveness, Adenosine Triphosphate, Integrins, Cell Proliferation, Cell Movement, Gene Expression Regulation, Neoplastic, Receptors, Purinergic P2Y2 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > London Centre for Nanotechnology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10169871 |
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