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SORLA regulates endosomal trafficking and oncogenic fitness of HER2

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  • Mika Pietilä, University of Turku
  • ,
  • Pranshu Sahgal, University of Turku
  • ,
  • Emilia Peuhu, University of Turku
  • ,
  • Niklas Z. Jäntti, University of Turku
  • ,
  • Ilkka Paatero, University of Turku
  • ,
  • Elisa Närvä, University of Turku
  • ,
  • Hussein Al-Akhrass, University of Turku
  • ,
  • Johanna Lilja, University of Turku
  • ,
  • Maria Georgiadou, University of Turku
  • ,
  • Olav M. Andersen
  • Artur Padzik, University of Turku
  • ,
  • Harri Sihto, Helsingin yliopisto
  • ,
  • Heikki Joensuu, Helsingin yliopisto
  • ,
  • Matias Blomqvist, Turku University Hospital
  • ,
  • Irena Saarinen, Turku University Hospital
  • ,
  • Peter J. Boström, University of Turku
  • ,
  • Pekka Taimen, Turku University Hospital
  • ,
  • Johanna Ivaska, University of Turku

The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

Original languageEnglish
Article number2340
JournalNature Communications
Volume10
Issue1
Pages (from-to)1-16
Number of pages16
ISSN2041-1723
DOIs
Publication statusPublished - May 2019

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