[en] Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.
Disciplines :
Oncology
Author, co-author :
Gupta, Suprit ; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA
Yano, Julian; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA
Mercier, Vincent; Department of Biochemistry, University of Geneva, Geneva, Switzerland
Htwe, Htet Htwe; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA
Shin, Hijai R ; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Rademaker, Gilles ; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA
Cakir, Zeynep; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA
Ituarte, Thomas; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA
Wen, Kwun W; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Kim, Grace E; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Zoncu, Roberto ; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Roux, Aurélien ; Department of Biochemistry, University of Geneva, Geneva, Switzerland
Dawson, David W; Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Perera, Rushika M ; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu ; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu
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