SORLA regulates endosomal trafficking and oncogenic fitness of HER2

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Pietilä , M , Sahgal , P , Peuhu , E , Jäntti , N Z , Paatero , I , Närvä , E , Al-Akhrass , H , Lilja , J , Georgiadou , M , Andersen , O M , Padzik , A , Sihto , H , Joensuu , H , Blomqvist , M , Saarinen , I , Boström , P J , Taimen , P & Ivaska , J 2019 , ' SORLA regulates endosomal trafficking and oncogenic fitness of HER2 ' , Nature Communications , vol. 10 , 2340 .

Title: SORLA regulates endosomal trafficking and oncogenic fitness of HER2
Author: Pietilä, Mika; Sahgal, Pranshu; Peuhu, Emilia; Jäntti, Niklas Z.; Paatero, Ilkka; Närvä, Elisa; Al-Akhrass, Hussein; Lilja, Johanna; Georgiadou, Maria; Andersen, Olav M.; Padzik, Artur; Sihto, Harri; Joensuu, Heikki; Blomqvist, Matias; Saarinen, Irena; Boström, Peter J.; Taimen, Pekka; Ivaska, Johanna
Contributor organization: Department of Pathology
Department of Oncology
CAN-PRO - Translational Cancer Medicine Program
HUS Comprehensive Cancer Center
Research Programs Unit
Heikki Joensuu / Principal Investigator
Date: 2019-05-28
Language: eng
Number of pages: 16
Belongs to series: Nature Communications
ISSN: 2041-1723
Abstract: 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.
3122 Cancers
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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