Close

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

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:

  1. 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?
  2. 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?
  3. 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?
  4. 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

Read preprint (No Ratings Yet)

Author's response

Rushika M. Perera, Ph.D. shared

  1. 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.
  2. 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.
  3. 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.
  4. 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).

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cancer biology category:

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Anticancer agents: Discovery and clinical use

Preprints that describe the discovery of anticancer agents and their clinical use. Includes both small molecules and macromolecules like biologics.

 



List by Zhang-He Goh

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

 



List by Joseph Jose Thottacherry

Also in the cell biology category:

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

preLights peer support – preprints of interest

This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.

 



List by preLights peer support

The Society for Developmental Biology 82nd Annual Meeting

This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.

 



List by Joyce Yu, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.

 



List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Dey Lab, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage
Close