CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake

  1. Savvas Nikolaou
  2. Amelie Juin
  3. Jamie A Whitelaw
  4. Nikki R Paul
  5. Loic Fort
  6. Colin Nixon
  7. Heather J Spence
  8. Sheila Bryson
  9. Laura M Machesky  Is a corresponding author
  1. Cancer Research UK Beatson Institute, United Kingdom
  2. Vanderbilt University, United States
  3. University of Cambridge, United Kingdom

Abstract

Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signaling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53-driven pancreatic cancer. Deletion of Cyrib (the gene encoding CYRI-B protein) accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a potential role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of the lysophosphatidic acid receptor-1. Overall, we implicate CYRI-B as a mediator of growth and signaling in pancreatic cancer, providing new insights into pathways controlling metastasis.

Data availability

All Western blot and numerical data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for all graphs and western blots.

Article and author information

Author details

  1. Savvas Nikolaou

    Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Amelie Juin

    Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Jamie A Whitelaw

    Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6739-1032
  4. Nikki R Paul

    Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Loic Fort

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6939-3621
  6. Colin Nixon

    Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8085-2160
  7. Heather J Spence

    Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Sheila Bryson

    Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Laura M Machesky

    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    lmm202@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7592-9856

Funding

Cancer Research UK (A24452)

  • Laura M Machesky

Cancer Research UK (A17196)

  • Amelie Juin
  • Jamie A Whitelaw
  • Nikki R Paul
  • Loic Fort
  • Colin Nixon
  • Heather J Spence
  • Sheila Bryson
  • Laura M Machesky

Cancer Research UK (A31287)

  • Amelie Juin
  • Jamie A Whitelaw
  • Nikki R Paul
  • Loic Fort
  • Colin Nixon
  • Heather J Spence
  • Sheila Bryson
  • Laura M Machesky

EPSRC UKRI (EP/T00213/1)

  • Laura M Machesky

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

Reviewing Editor

  1. Erica A Golemis, Fox Chase Cancer Center, United States

Ethics

Animal experimentation: Mice were maintained by the Biological Services Unit staff according to the UK home office regulations and instructions. The experiments were approved by the local Animal Welfare and Ethical Review Body (AWERB) of the University of Glasgow and performed under UK Home office licence PE494BE48 to LMM.

Version history

  1. Received: September 26, 2022
  2. Accepted: May 6, 2024
  3. Accepted Manuscript published: May 7, 2024 (version 1)

Copyright

© 2024, Nikolaou 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. Savvas Nikolaou
  2. Amelie Juin
  3. Jamie A Whitelaw
  4. Nikki R Paul
  5. Loic Fort
  6. Colin Nixon
  7. Heather J Spence
  8. Sheila Bryson
  9. Laura M Machesky
(2024)
CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake
eLife 13:e83712.
https://doi.org/10.7554/eLife.83712

Share this article

https://doi.org/10.7554/eLife.83712

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