Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth
Copyright policy )Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth
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.
- University of California, Berkeley United States
- University of California, San Francisco United States
- University of California System United States
- University of Geneva Switzerland
- University of Liège Belgium
Intracellular Membranes/metabolism, Pancreatic Neoplasms/pathology, Oncologie, Muscle Proteins, Intracellular Membranes/pathology, Inbred C57BL, Lysosomes/metabolism, Medical and Health Sciences, Transgenic, Mice, 2.1 Biological and endogenous factors, Lysosomes/genetics, Human health sciences, Muscle Proteins/metabolism, Cancer, Muscle Proteins/genetics, Pancreatic Neoplasms/metabolism, Tumor, Biological Sciences, Prognosis, MYOF protein, human, Tumor Burden, Gene Expression Regulation, Neoplastic, Oncology, Biomarkers, Tumor/genetics, Signal Transduction, 610, Mice, Transgenic, 612, Sciences de la santé humaine, Cell Line, Pancreatic Cancer, Rare Diseases, Calcium-Binding Proteins/metabolism, Cell Line, Tumor, Biomarkers, Tumor, Animals, Humans, Lysosomes/pathology, Membrane Proteins/genetics, Cell Proliferation, Neoplastic, Calcium-Binding Proteins/genetics, Calcium-Binding Proteins, Membrane Proteins, Cell Biology, Intracellular Membranes, Pancreatic Neoplasms/genetics, Mice, Inbred C57BL, Pancreatic Neoplasms, Gene Expression Regulation, Biochemistry and cell biology, Biomarkers, Tumor/metabolism, myoferlin protein, mouse, Membrane Proteins/metabolism, Biochemistry and Cell Biology, Generic health relevance, Digestive Diseases, Lysosomes, Biomarkers, Developmental Biology, ddc: ddc:540
Intracellular Membranes/metabolism, Pancreatic Neoplasms/pathology, Oncologie, Muscle Proteins, Intracellular Membranes/pathology, Inbred C57BL, Lysosomes/metabolism, Medical and Health Sciences, Transgenic, Mice, 2.1 Biological and endogenous factors, Lysosomes/genetics, Human health sciences, Muscle Proteins/metabolism, Cancer, Muscle Proteins/genetics, Pancreatic Neoplasms/metabolism, Tumor, Biological Sciences, Prognosis, MYOF protein, human, Tumor Burden, Gene Expression Regulation, Neoplastic, Oncology, Biomarkers, Tumor/genetics, Signal Transduction, 610, Mice, Transgenic, 612, Sciences de la santé humaine, Cell Line, Pancreatic Cancer, Rare Diseases, Calcium-Binding Proteins/metabolism, Cell Line, Tumor, Biomarkers, Tumor, Animals, Humans, Lysosomes/pathology, Membrane Proteins/genetics, Cell Proliferation, Neoplastic, Calcium-Binding Proteins/genetics, Calcium-Binding Proteins, Membrane Proteins, Cell Biology, Intracellular Membranes, Pancreatic Neoplasms/genetics, Mice, Inbred C57BL, Pancreatic Neoplasms, Gene Expression Regulation, Biochemistry and cell biology, Biomarkers, Tumor/metabolism, myoferlin protein, mouse, Membrane Proteins/metabolism, Biochemistry and Cell Biology, Generic health relevance, Digestive Diseases, Lysosomes, Biomarkers, Developmental Biology, ddc: ddc:540
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