SORLA regulates endosomal trafficking and oncogenic fitness of HER2

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

doi:10.1038/s41467-019-10275-0

SORLA regulates endosomal trafficking and oncogenic fitness of HER2

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

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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.

Original language	Undefined/Unknown
Pages (from-to)	–
Number of pages	16
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-10275-0
Publication status	Published - 2019
MoE publication type	A1 Journal article-refereed

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10.1038/s41467-019-10275-0

Cite this

Pietilä, M., Sahgal, P., Peuhu, E., Jäntti, N., 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, 10, –. https://doi.org/10.1038/s41467-019-10275-0

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title = "SORLA regulates endosomal trafficking and oncogenic fitness of HER2",

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.",

author = "Mika Pietil{\"a} and Pranshu Sahgal and Emilia Peuhu and Niklas J{\"a}ntti and Ilkka Paatero and Elisa N{\"a}rv{\"a} and Hussein Al-Akhrass and Johanna Lilja and Maria Georgiadou and Andersen, {Olav M.} and Artur Padzik and Harri Sihto and Heikki Joensuu and Matias Blomqvist and Irena Saarinen and Bostr{\"o}m, {Peter J.} and Pekka Taimen and Johanna Ivaska",

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Pietilä, M, Sahgal, P, Peuhu, E, Jäntti, N, Paatero, I, Närvä, E, Al-Akhrass, H, Lilja, J, Georgiadou, M, Andersen, OM, Padzik, A, Sihto, H, Joensuu, H, Blomqvist, M, Saarinen, I, Boström, PJ, Taimen, P & Ivaska, J 2019, 'SORLA regulates endosomal trafficking and oncogenic fitness of HER2', Nature Communications, vol. 10, pp. –. https://doi.org/10.1038/s41467-019-10275-0

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T1 - SORLA regulates endosomal trafficking and oncogenic fitness of HER2

AU - Pietilä, Mika

AU - Sahgal, Pranshu

AU - Peuhu, Emilia

AU - Jäntti, Niklas

AU - Paatero, Ilkka

AU - Närvä, Elisa

AU - Al-Akhrass, Hussein

AU - Lilja, Johanna

AU - Georgiadou, Maria

AU - Andersen, Olav M.

AU - Padzik, Artur

AU - Sihto, Harri

AU - Joensuu, Heikki

AU - Blomqvist, Matias

AU - Saarinen, Irena

AU - Boström, Peter J.

AU - Taimen, Pekka

AU - Ivaska, Johanna

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-019-10275-0

DO - 10.1038/s41467-019-10275-0

M3 - Artikel

SN - 2041-1723

VL - 10

SP - –

JO - Nature Communications

JF - Nature Communications

ER -