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

Suprit Gupta, Julian Yano, Htet Htwe Htwe, Hijai R. Shin, Zeynep Cakir, Thomas Ituarte, Kwun W. Wen, Grace E. Kim, Roberto Zoncu, David W. Dawson, Rushika M. Perera

Preprint posted on 4 January 2021 https://www.biorxiv.org/content/10.1101/2021.01.04.425106v1

Article now published in Nature Cell Biology at http://dx.doi.org/10.1038/s41556-021-00644-7

Ferlins to the rescue! Plasma membrane repair protein Myoferlin relocates to lysosomes in pancreatic cancer cells to protect lysosomes against microtears in their membrane.

Selected by Berrak Ugur

Categories: cancer biology, cell biology

Background:

Proper lysosomal activity is essential for regular cell function and lysosomal defects are associated with many diseases including cancer (Carmona-Gutierrez et al., 2016; Platt et al., 2012). Among cancers, pancreatic ductal adenocarcinoma (PDA) is known to rely on enhanced autophagy and lysosomal function (Perera et al., 2015; Yang et al., 2011). Although it is known that PDA cells have increased lysosomal activity, cancer specific pathways to ensure proper lysosomal function are not known.

Key Findings:

To identify lysosomal factors involved in PDA, the authors purify intact lysosomes from PDA and regular cell lines and compare the proteomic profile of these lysosomes. Through this analysis, they identify two Ferlin proteins, Myoferlin (MYOF) and Dysferlin (DysF) as the most enriched proteins in PDA lysosomes (MYOF ~30 times, DysF ~90 times enriched). The authors confirm these findings by showing that MYOF is indeed present in PDA lysosomes and bound to the lysosomal membrane. Given its known localization at the plasma membrane and its role in regulating membrane repair, the authors speculate whether Myoferlin may be targeted to lysosomes to specifically repair the lysosomal membrane (Bansal and Campbell, 2004; Bansal et al., 2003; Doherty and McNally, 2003). To test this hypothesis, they treat the lysosomes with various stressors known to impair the lysosome membrane. They observe that PDA cells last longer and retain markers of nutrient signaling in response to treatment when compared to regular pancreatic cells. The authors reason that this enhanced lysosomal protection in PDA cells may depend on MYOF, as it was highly enriched in PDA cells. To test this idea, they knock-out MYOF and show that loss of MYOF in PDA cells lead to various lysosomal defects and absence of protection against stressors. To test if MYOF-dependent lysosome protection is related to autophagy or vesicular trafficking, they knock-down several factors involved in autophagy in MYOF KO cells and observe that lysosomal defects are suppressed. Along these lines, the authors show that artificially recruiting MYOF to lysosomes in non-PDA cells protects them against stressors and that this protection is specifically regulated by the N terminal C2 domains of MYOF. Next, they confirm that MYOF expression is also increased in a mouse model of pancreatic ductal adenocarcinoma. Moreover, they report that reducing MYOF levels leads to a decrease in tumor growth in these models. Supporting these observations, they reiterate that data from The Cancer Genome Atlas show that high MYOF expression is correlated with worse survival of PDA patients. Overall, this study pinpoints MYOF as novel regulator of the lysosomal membrane and an important player in pancreatic ductal adenocarcinoma.

Take home messages:

Myoferlin and Dysferlin are enriched on lysosomes isolated from pancreatic ductal adenocarcinoma (PDA).
PDA lysosomes are more resistant to lysosome membrane damage
MYOF is important for proper lysosome function in PDA cells
Loss of MYOF leads to reduced tumor growth

Fig.1 Model of how MYOF is regulating PDA lysosomes. MYOF is localized to lysosomes in PDA cells and regulates them agains stress. Loss of MYOF leads to membrane damage and recruitment of factors such as ESCRT and GAL3. doi: https://doi.org/10.1101/2021.01.04.425106

Why I liked this study: This preprint shows that a protein previously implicated in plasma membrane repair can localize to lysosomes to protect them against microtears in the lysosomal membrane. It is very tempting to think that MYOF has the capacity to relocate to different membranes to protect against insults. I am curious to see if MYOF or other ferlins have such a common repair role.

Questions:

What is the partner of MYOF that recruits it to lysosomes in PDA cells? Do you speculate that it is a PDA cell specific metabolite/factor or some other commonly known factors such as Rab7? Do you think that a dominant-negative Rab7 would prevent the resilience of PDA cells against LLOMe treatment?
MYOF overexpression is observed in different cancers in addition to pancreas adenocarcinoma (Dong et al., 2019). Do you think that your observation about MYOF’s lysosomal function in PDA is applicable to other cancer types?
Is it possible that the suppression observed with knockdown of ATG3 or ATG7 in MYOF KO is due to relieving autophagy cargo burden? Do you think manipulating vesicular trafficking with some drugs or KD of genes known in vesicular trafficking would cause a similar suppression?
Do you think that artificially recruiting MYOF to other organelles (such as mitochondria or peroxisomes) would prevent them against insults to their (outer) membrane?

References:

Bansal, D., and Campbell, K.P. (2004). Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol. 14, 206–213.

Bansal, D., Miyake, K., Vogel, S.S., Groh, S., Chen, C.-C., Williamson, R., McNeil, P.L., and Campbell, K.P. (2003). Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172.

Carmona-Gutierrez, D., Hughes, A.L., Madeo, F., and Ruckenstuhl, C. (2016). The crucial impact of lysosomes in aging and longevity. Ageing Res. Rev. 32, 2–12.

Doherty, K.R., and McNally, E.M. (2003). Repairing the tears: dysferlin in muscle membrane repair. Trends Mol. Med. 9, 327–330.

Dong, Y., Kang, H., Liu, H., Wang, J., Guo, Q., Song, C., Sun, Y., Zhang, Y., Zhang, H., Zhang, Z., et al. (2019). Myoferlin, a Membrane Protein with Emerging Oncogenic Roles (Hindawi).

Perera, R.M., Stoykova, S., Nicolay, B.N., Ross, K.N., Fitamant, J., Boukhali, M., Lengrand, J., Deshpande, V., Selig, M.K., Ferrone, C.R., et al. (2015). Transcriptional control of the autophagy-lysosome system in pancreatic cancer. Nature 524, 361–365.

Platt, F.M., Boland, B., and van der Spoel, A.C. (2012). Lysosomal storage disorders: The cellular impact of lysosomal dysfunction. J. Cell Biol. 199, 723–734.

Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., Bause, A., Li, Y., Stommel, J.M., Dell’Antonio, G., et al. (2011). Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729.

Tags: ferlin, lysosome, membrane repair, pancreatic cancer

Posted on: 27 January 2021

doi: https://doi.org/10.1242/prelights.27108

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Author's response

Rushika M. Perera, Ph.D. shared

Great question! it is likely a cancer specific factor that enables this unique localization. This could be a protein binding partner, a metabolite or a unique component of the lysosome membrane of cancer cells. We are in the process of addressing this important point.
In the revised version of our study we do explore additional cancer types previously reported to also expression high levels of MYOF. Future studies will help to establish whether its function at the lysosome in PDA cells is unique or common in other cancers as well.
Yes ! We think relieving the elevated trafficking burden characteristic of PDA cells alleviates some of the lysosomal stress associated with MYOF loss. Given that there are several important trafficking pathways in these cells (macropinocytosis and classical endocytosis), it is likely that suppression of these pathways may also have a similar effect.
This is an interesting point. It’s possible that there are specific features of cancer lysosomes that not only aid in the recruitment of MYOF to the membrane but also ensure its function. Whether this could also happen at other organelle membranes is unclear. The function of MYOF may also be best suited for repairing specific types of membrane damage, which may also restrict its activity to specific cellular locations (eg. plasma membrane and lysosome membrane).

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

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