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Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion

Elena Tomas Bort1,2, Megan D Joseph3,4, Qiaoying Wang1

  • 1Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Elife
|March 21, 2023
PubMed

Insights

Pancreatic cancer survival remains poor. Targeting the P2Y2 receptor and its interaction with integrins offers a new therapeutic strategy by inhibiting ATP-driven cancer cell invasion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) has dismal survival rates.
  • Elevated extracellular ATP suggests the purinergic axis as a therapeutic target.
  • The purinergic axis influences fibrosis, inflammation, and immune responses in PDAC.

Purpose of the Study:

  • Identify key purinergic axis members impacting PDAC patient survival.
  • Investigate the role of the P2Y2 receptor (P2RY2) in PDAC invasion.
  • Elucidate the mechanism of ATP-driven invasion involving P2Y2 and integrins.

Main Methods:

  • Bioinformatic analysis of public databases to assess purinome members.
  • 3D spheroid invasion assays to study P2Y2-mediated invasion.
  • Genetic and pharmacological manipulations to probe P2Y2-integrin interactions.
  • DNA-PAINT super-resolution microscopy to visualize P2Y2 and integrin αV distribution.

Main Results:

  • P2RY2 showed the strongest association with hypoxia, high cancer cell expression, and poor survival.
  • Extracellular ATP-driven invasion was critically dependent on the P2Y2 receptor.
  • ATP-driven invasion requires direct protein-protein interactions between P2Y2 and integrin αV.
  • P2Y2 regulates integrin αV plasma membrane localization and downstream signaling.

Conclusions:

  • P2Y2 is a critical mediator of ATP-driven pancreatic cancer cell invasion.
  • A novel GPCR-integrin interaction between P2Y2 and integrin αV drives cancer invasion.
  • This P2Y2-integrin axis represents a potential therapeutic target for PDAC.
Keywords:
3D modellingDNA-PAINTcancer biologycell biologyhumaninvasionpancreatic cancerpurinergic signalling

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