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SORLA regulates endosomal trafficking and oncogenic fitness of HER2

Mika Pietilä1, Pranshu Sahgal2, Emilia Peuhu2

  • 1Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland. mika.pietila@utu.fi.

Nature Communications
|May 30, 2019
PubMed

Insights

Sortilin-related receptor 1 (SORLA) regulates human epidermal growth factor receptor 2 (HER2) trafficking in cancer cells. SORLA depletion impairs HER2 signaling and tumor growth, revealing new therapeutic vulnerabilities.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background:

  • Human epidermal growth factor receptor 2 (HER2) is a key oncogene in various cancers.
  • HER2 signaling is regulated by its subcellular localization and endosomal trafficking.
  • The role of endosomal trafficking in HER2 regulation is not fully understood, with a prevailing view of cell surface retention.

Purpose of the Study:

  • To investigate the role of sortilin-related receptor 1 (SORLA) in HER2 trafficking and signaling.
  • To determine the impact of SORLA on HER2-driven tumor growth and response to therapy.

Main Methods:

  • Co-immunoprecipitation assays to assess SORLA-HER2 interaction.
  • Analysis of HER2 subcellular distribution upon SORLA modulation.
  • Assessment of HER2 signaling pathways and in vivo tumor growth in SORLA-depleted models.
  • Evaluation of lysosome function and drug sensitivity after SORLA silencing.

Main Results:

  • SORLA co-precipitates with HER2 and promotes its recycling to the plasma membrane.
  • SORLA levels correlate with HER2 levels in cancer cell lines and bladder cancers.
  • SORLA depletion leads to HER2 lysosomal degradation, impaired signaling, and reduced tumor growth.
  • SORLA silencing disrupts lysosome function and sensitizes cancer cells to lysosome-targeting drugs.

Conclusions:

  • SORLA plays a critical role in regulating HER2 subcellular distribution and signaling.
  • SORLA-dependent endosomal trafficking represents a potential vulnerability in HER2-driven cancers.
  • Targeting SORLA or related pathways may offer novel therapeutic strategies for HER2-positive cancers.

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