Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth

Nat Cell Biol. 2021 Mar;23(3):232-242. doi: 10.1038/s41556-021-00644-7. Epub 2021 Mar 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Membranes / metabolism*
  • Intracellular Membranes / pathology
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Signal Transduction
  • Tumor Burden


  • Biomarkers, Tumor
  • Calcium-Binding Proteins
  • MYOF protein, human
  • Membrane Proteins
  • Muscle Proteins
  • myoferlin protein, mouse