MYOF Reduces Lysosome Membrane Stress to Promote Pancreatic Cancer

Due to higher rates of autophagy and macropinocytosis, lysosomal recycling plays a more important role in pancreatic ductal adenocarcinoma (PDAC) cells compared with normal pancreatic cells. Upregulation of lysosome biogenesis in PDAC cells is well established, but whether cancer-specific mechanisms contributing to lysosome membrane integrity also contribute to greater lysosomal recycling capabilities in PDAC cells is not known. To identify proteins involved in lysosome membrane maintenance, Gupta and colleagues performed affinity purification of lysosomes from PDAC and non-PDAC cells and discovered that the plasma membrane repair factor Myoferlin (MYOF) was highly enriched in PDAC cells. MYOF localized to lysosome surfaces in PDAC cells, and PDAC lysosomes were more resistant to acute damage via lysosome membrane–rupturing agents. To investigate whether MYOF contributed to protection against lysosome membrane damage, MYOF was knocked down via RNA interference or knocked out via CRISPR–Cas9-mediated mutagenesis, leading to dysfunctional lysosome morphology. When cargo trafficking to the lysosome was inhibited by blocking autophagosome formation, the lysosome defects associated with MYOF suppression were reversed, suggesting that MYOF functioned to mitigate lysosome membrane stress that results from high levels of vesicle trafficking observed in PDAC cells. Upon lysosome membrane damage, lysosomal targeting of MYOF was sufficient to delay the recruitment of membrane repair factors that typically resolve lysosome damage, and further studies identified the three N-terminal C2 domains of MYOF as critical for mediating protective function. Accordingly, MYOF suppression in PDAC cells reduced in vitro colony formation and inhibited in vivo xenograft tumor growth. Importantly, MYOF mRNA and MYOF protein levels were elevated in human PDAC tumor tissues compared with normal tissues, and high expression of MYOF was associated with decreased patient survival in two independent cohorts (n = 136; n = 185) in The Cancer Genome Atlas. This work reveals a protective pathway maintaining lysosome membrane integrity in PDAC cells and suggests MYOF as a potential therapeutic target in pancreatic cancer.

Gupta S, Yano J, Mercier V, Htwe HH, Shin HR, Rademaker G, et al. Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth. Nat Cell Biol 2021;23:232–42.

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