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A direct role for Met endocytosis in tumorigenesis

Carine Joffre1, Rachel Barrow, Ludovic Ménard

  • 1Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

Nature Cell Biology
|June 7, 2011
PubMed

Insights

Altered endocytosis and recycling of tumor-associated Met mutants drive cancer growth. Inhibiting endocytosis suppressed tumor formation, suggesting endosomal signaling is key to receptor tyrosine kinase (RTK) tumorigenesis.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Receptor tyrosine kinase (RTK) signaling is crucial for cell function.
  • Endocytosis and signal compartmentalization by RTKs play a role in cell regulation.
  • Tumorigenic RTK mutations can alter their endocytic trafficking and signaling.

Purpose of the Study:

  • To investigate the direct link between endocytosis and tumorigenicity of tumor-associated Met mutants.
  • To explore the role of altered endocytic trafficking in RTK-driven oncogenesis.
  • To determine if endocytosis inhibition can be a therapeutic strategy for Met-mutant cancers.

Main Methods:

  • Utilizing tumor-associated Met-activating mutations in cellular models.
  • Analyzing endocytosis, recycling, and degradation rates of Met mutants.
  • Assessing cell migration, actin cytoskeleton organization, and Rac1 activation.
  • Evaluating the impact of endocytosis inhibition on anchorage-independent growth, in vivo tumorigenesis, and metastasis.
  • Testing sensitivity of Met mutants to tyrosine kinase inhibitors and endocytosis inhibitors.

Main Results:

  • Met mutants showed increased endocytosis/recycling and decreased degradation, leading to endosomal accumulation.
  • Mutant accumulation on endosomes activated Rac1, disrupted actin stress fibers, and enhanced cell migration.
  • Blocking endocytosis significantly inhibited anchorage-independent growth, in vivo tumorigenesis, and metastasis of Met mutants.
  • Endocytosis inhibition was effective even for a Met mutant resistant to a specific tyrosine kinase inhibitor.
  • Met activation alone was not solely responsible for oncogenicity; altered endocytic trafficking was critical.

Conclusions:

  • Oncogenicity of Met mutants is driven by both activation and altered endocytic trafficking.
  • Endosomal signaling compartments are crucial regulatory mechanisms in RTK-dependent tumorigenesis.
  • Targeting endocytic trafficking pathways represents a potential therapeutic strategy for cancers driven by Met mutants.

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