Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The mass spectrometry data have been deposited in MassIVE with the accession code MSV000086769. Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author on reasonable request.
References
Lawrence, R. E. & Zoncu, R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat. Cell Biol. 21, 133–142 (2019).
Perera, R. M. & Zoncu, R. The lysosome as a regulatory hub. Annu. Rev. Cell Dev. Biol. 32, 223–253 (2016).
Ballabio, A. & Bonifacino, J. S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101–118 (2020).
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
Perera, R. M. et al. Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).
Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).
Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).
Yamamoto, K. et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581, 100–105 (2020).
Perera, R. M., Di Malta, C. & Ballabio, A. MiT/TFE family of transcription factors, lysosomes, and cancer. Annu Rev. Cancer Biol. 3, 203–222 (2019).
Papadopoulos, C., Kravic, B. & Meyer, H. Repair or lysophagy: dealing with damaged Lysosomes. J. Mol. Biol. 432, 231–239 (2020).
Vietri, M., Radulovic, M. & Stenmark, H. The many functions of ESCRTs. Nat. Rev. Mol. Cell Biol. 21, 25–42 (2020).
Radulovic, M. et al. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. https://doi.org/10.15252/embj.201899753 (2018).
Skowyra, M. L., Schlesinger, P. H., Naismith, T. V. & Hanson, P. I. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science https://doi.org/10.1126/science.aar5078 (2018).
Hung, Y. H., Chen, L. M., Yang, J. Y. & Yang, W. Y. Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat. Commun. 4, 2111 (2013).
Jia, J. et al. Galectins control mTOR in response to endomembrane damage. Mol. Cell 70, 120–135 (2018).
Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013).
Abu-Remaileh, M. et al. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358, 807–813 (2017).
Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).
Bansal, D. & Campbell, K. P. Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol. 14, 206–213 (2004).
Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003).
Davis, D. B., Delmonte, A. J., Ly, C. T. & McNally, E. M. Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Hum. Mol. Genet. 9, 217–226 (2000).
Doherty, K. R. et al. Normal myoblast fusion requires myoferlin. Development 132, 5565–5575 (2005).
Lek, A., Evesson, F. J., Sutton, R. B., North, K. N. & Cooper, S. T. Ferlins: regulators of vesicle fusion for auditory neurotransmission, receptor trafficking and membrane repair. Traffic 13, 185–194 (2012).
Bashir, R. et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat. Genet. 20, 37–42 (1998).
Liu, J. et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat. Genet. 20, 31–36 (1998).
Repnik, U. et al. l-leucyl-l-leucine methyl ester does not release cysteine cathepsins to the cytosol but inactivates them in transiently permeabilized lysosomes. J. Cell Sci. 130, 3124–3140 (2017).
Mercier, V. et al. Endosomal membrane tension regulates ESCRT-III-dependent intra-lumenal vesicle formation. Nat. Cell Biol. 22, 947–959 (2020).
Chauhan, S. et al. TRIMs and galectins globally cooperate and TRIM16 and Galectin-3 co-direct autophagy in endomembrane damage homeostasis. Dev. Cell 39, 13–27 (2016).
Thurston, T. L., Wandel, M. P., von Muhlinen, N., Foeglein, A. & Randow, F. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414–418 (2012).
Aits, S. et al. Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. Autophagy 11, 1408–1424 (2015).
Kilpatrick, B. S., Eden, E. R., Hockey, L. N., Futter, C. E. & Patel, S. Methods for monitoring lysosomal morphology. Methods Cell. Biol. 126, 1–19 (2015).
Platt, F. M., Boland, B. & van der Spoel, A. C. Lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J. Cell Biol. 199, 723–734 (2012).
Mauthe, M. et al. Chloroquine inhibits autophagic flux by decreasing autophagosome–lysosome fusion. Autophagy 14, 1435–1455 (2018).
Colom, A. et al. A fluorescent membrane tension probe. Nat. Chem. 10, 1118–1125 (2018).
Goujon, A. et al. Mechanosensitive fluorescent probes to image membrane tension in mitochondria, endoplasmic reticulum, and lysosomes. J. Am. Chem. Soc. 141, 3380–3384 (2019).
Lawrence, R. E. et al. A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase–Ragulator lysosomal scaffold. Nat. Cell Biol. 20, 1052–1063 (2018).
Liberles, S. D., Diver, S. T., Austin, D. J. & Schreiber, S. L. Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid screen. Proc. Natl Acad. Sci. USA 94, 7825–7830 (1997).
Davis, D. B., Doherty, K. R., Delmonte, A. J. & McNally, E. M. Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains. J. Biol. Chem. 277, 22883–22888 (2002).
Marty, N. J., Holman, C. L., Abdullah, N. & Johnson, C. P. The C2 domains of otoferlin, dysferlin, and myoferlin alter the packing of lipid bilayers. Biochemistry 52, 5585–5592 (2013).
Doherty, K. R. et al. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J. Biol. Chem. 283, 20252–20260 (2008).
Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
Weber, R. A. et al. Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation. Mol. Cell 77, 645–655 e647 (2020).
Yambire, K. F. et al. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. eLife https://doi.org/10.7554/eLife.51031 (2019).
Xu, H. & Ren, D. Lysosomal physiology. Annu Rev. Physiol. 77, 57–80 (2015).
Dong, R. et al. Endosome–ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell 166, 408–423 (2016).
Lim, C. Y. et al. ER–lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann–Pick type C. Nat. Cell Biol. 21, 1206–1218 (2019).
Rademaker, G. et al. Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. Oncogene 37, 4398–4412 (2018).
Rademaker, G. et al. Human colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis. Oncogenesis 8, 21 (2019).
Petersen, N. H. et al. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell 24, 379–393 (2013).
Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists. Nucleic Acids Res. 47, W191–W198 (2019).
Liang, X. et al. Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection. J. Biotechnol. 208, 44–53 (2015).
Manuyakorn, A. et al. Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704. J. Clin. Oncol. 28, 1358–1365 (2010).
Acknowledgements
We thank all of the members of the Perera and Debnath laboratories for their helpful discussions. R.M.P. is the Nadia’s Gift Foundation Innovator of the Damon Runyon Cancer Research Foundation (grant no. DRR-46-17) and is additionally supported by an NIH Director’s New Innovator Award (grant no. 1DP2CA216364), the Pancreatic Cancer Action Network Career Development Award and the Hirshberg Foundation for Pancreatic Cancer. H.R.S. is supported by an AACR–Amgen fellowship in Clinical/Translational Cancer Research. G.R. is supported by the Belgian American Educational Foundation and the Léon Fredericq Foundation. R.Z. is supported by grants from the NIH (grant nos R01GM127763 and R01GM130995), a Damon Runyon–Rachleff Innovator Award and an Edward Mallinckrodt, Jr Foundation Grant. A.R. is supported by a Human Frontier Science Program Young Investigator Grant (grant no. RGY0076/2009-C), the Swiss National Fund for Research and an European Research Council Consolidator Grant. D.W.D. receives support from the Hirshberg Foundation for Pancreatic Cancer Research. We thank R. Zalpuri at the University of California, Berkeley Electron Microscope Laboratory for advice and assistance with electron-microscopy sample preparation and data collection.
Author information
Authors and Affiliations
Contributions
S.G. performed the majority of the experiments and drafted the manuscript. J.Y. developed the FKBP-FRB* assay and conducted surface biotinylation experiments, molecular cloning and data analysis. V.M. conducted FLIM experiments and data analysis. H.H.H. assisted with the mouse experiments and immunohistochemistry. H.R.S. performed the electron microscopy. G.R. performed RT–qPCR and data analysis. Z.C. performed the proteinase K protection assay. T.I. conducted data and pathway analysis. K.W.W. and G.E.K. provided pathology analysis of patient samples. R.Z. provided intellectual feedback and supervised H.R.S. A.R. provided intellectual feedback and supervised V.M. D.W.D provided the PDA tissue microarray and conducted independent pathology analysis and statistical testing. R.M.P. conceived the project, supervised the research, and wrote and edited the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information Nature Cell Biology thanks Harald Stenmark, Kay Macleod and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data
Extended Data Fig. 1 MYOF is a novel lysosomal membrane protein in PDA cells.
a, Co-localization of T192–mRFP-3xHA and endogenous LAMP2 in KP4 cells. b, RT-qPCR analysis of MYOF and DYSF mRNA levels across 10 human PDA cell lines and 3 non-PDA cell lines. Data is representative of n=3 independent biological replicate experiments. c,d, Immunofluorescence staining of MYOF–HA (green) and LAMP2 (red) in PDA cell lines (MiaPaCa, PaTu8902 and Panc0203) (c) and non-PDA (U20S and HPDE) cell lines (d). Arrowheads show examples of co-localization. e, Treatment of KP4, MiaPaCa and PaTu8988T cells with 75nM BafA1 for the indicated times causes an increase in p62 levels but not MYOF or DYSF. Graph shows the quantification of normalized fold change relative to LAMP1, averaged from 3 independent experiments. Data are mean ± s.d. Scale, 20μm for all panels. Statistics source data are provided.
Extended Data Fig. 2 PDA lysosomes are resistant to multiple membrane perturbing agents.
a, Time course of LysoTracker red staining in 293T and U20S cells following treatment with LLOMe. (293T, n= 86, 88, 88, 87 cells per time point ; U20S n= 69, 63, 69, 65 cells per time point). b, Immunoblot showing the expression of Cathepsin C and Cathepsin B in the indicated cell lines. Asterisk denotes cell lines used throughout the study. c, Immunofluorescence quantification of Magic Red assay-based cathepsin protease activity in n = 65 cells per cell line. d, Time course of LysoTracker red staining in HPDE and KP4 cells following treatment with 0.5M sucrose. e, Normalized fold change of LysoTracker staining. (HPDE, n = 64, 64, 65, 65 cells per time point; KP4, n = 64, 63, 63, 64 cells per time point). f, Time course of LysoTracker red staining in HPDE and KP4 cells following treatment with 100 μg/ml silica. g, Normalized fold change of LysoTracker staining. (HPDE, n = 65 cells per time point; KP4, n = 65 cells per time point). h, Immunoblots for the indicated proteins in MiaPaca cells following a time course of 1mM LLOMe treatment. i, Immunoblots for the indicated proteins in HPDE, KP4 and MiaPaca cells following treatment for 1hr with increasing doses of LLOMe. Scale, 20μm for all panels. For box-and-whisker plots centre lines indicate median values and whiskers represent minimum and maximum values. Data are mean ± s.d. P values determined by unpaired two-tailed Student’s t-tests. Statistics source data are provided. Unmodified blots are provided in Source Data Extended Data Fig. 2. Experiment depicted in b are representative of two independent experiments.
Extended Data Fig. 3 Recruitment of ESCRT proteins to PDA lysosomes is delayed following acute damage.
a-c, Time course of LLOMe (a), 0.5M sucrose (b), 100 μg/ml silica (c) treatment of HPDE and KP4 cells followed by immunofluorescence staining for ALIX (green) and LAMP1 (red). Graphs show the quantification of percentage co-localization of ALIX (LLOMe, n = 60 cells/condition for HPDE and KP4; sucrose, HPDE n = 13 fields/conditions, KP4 n= 13, 15, 15 fields/condition; silica, HPDE n = 14 fields/condition, KP4 n= 13, 13, 12 fields/condition) with LAMP1-positive lysosomes. d, Time course of LLOMe treatment of HPDE and KP4 cells followed by immunofluorescence staining for CHMP1A (green) and LAMP1 (red). e, Graph shows quantification of percentage co-localization of CHMP1A (n = 40 per cell line) with LAMP1-positive lysosomes. f, Immunoblot for the indicated proteins in lysosome fractions and flow through fractions isolated from HPDE- and KP4-T192–mRFP-3xHA stable cell lines treated with LLOMe for 10min. Scale, 20μm. Data are mean ± s.d. P values determined by unpaired two-tailed Student’s t-tests. Statistics source data are provided. Unmodified blots are provided in Source Data Extended Data Fig. 3. Experiment depicted in f are representative of two independent experiments.
Extended Data Fig. 4 MYOF loss leads to lysosome dysfunction in PDA cells.
a, Immunoblot of MYOF in KP4 and PaTu8902 cells. b, LAMP2 staining (arrowheads) in MYOF KO PaTu8902 cells. Graph shows lysosome diameter in control (Cas9; n = 252), MYOF KO #1 (n = 255) and MYOF KO #2 (n = 258) cells. c,d, LAMP2 staining (arrowheads) following shRNA-mediated knockdown of MYOF in PaTu8902 (c) and KP4 (d) cells. Graphs show lysosome diameter [PaTu8902 shGFP (n = 258), shMYOF#1 (n = 256), shMYOF#2 (n = 263); KP4 shGFP (n = 254), shMYOF#1 (n = 239), shMYOF#2 (n = 243) cells]. e, LysoTracker staining in KP4 cells following knockdown of MYOF. Graph shows normalized fold change in LysoTracker fluorescence in control (shGFP, n = 70 cells) and KD (shMYOF#1, n = 65; shMYOF#2, n = 77) conditions. f, Recruitment of CHMP1A (green) to LAMP1-positive lysosomes (red) in MYOF KO (#1, n = 60; #2, n = 61) relative to Cas9 control (n = 58) KP4 cells. Graph shows the percentage CHMP1A co-localization with LAMP1. g,h, Representative FLIM images (g) of lysosomes labelled with Lyso Flipper in KP4 cells 72hrs post-transfection with siCTRL (left) or siMYOF (right) and lifetime (Tau 1) measurements (h) from siCTRL and siMYOF transfected cells (n = 4 experiments). Scale, 10 µm. i, Lyso Flipper lifetime measurements from KP4 Cas9 and MYOF KO cells (n = 3 experiments). j, Galectin 3 (GAL3; green) and LAMP1 (red) staining following LLOMe treatment of KP4 Cas9 or MYOF KO cells (n = 60 cells/condition). k, LC3B staining in PaTu8902 cells in shGFP or shRNA MYOF knockdown cells (n = 14 fields per condition). Graph shows LC3B puncta per field. l, Degradation of macropinocytosed DQ-BSA in lysosomes [n = 54 (shGFP), 57 (shMYOF#1), 52 (shMYOF#2), n = 54 (BafA1) fluorescent spots/cell co-localizing with LAMP2-positive lysosomes]. m, Immunoblots from KP4 control (shGFP) or MYOF knockdown cells treated with or without 1mM LLOMe. Data are mean ± s.d. Scale, 20μm unless otherwise indicated. P values determined by unpaired two-tailed Student’s t-tests. Statistics source data are provided. Unmodified blots are provided in Source Data Extended Data Fig. 4. Experiment depicted in m are representative of two independent experiments.
Extended Data Fig. 5 Autophagy suppression reverses lysosome damage response in MYOF KO cells.
a, Immunoblot confirming shRNA-mediated knockdown of ATG3 and autophagy blockade in KP4 MYOF KO cells. b,c, Recruitment of CHMP1A (green) (b) or CHMP3 (green) (c) to lysosomes (LAMP1; red) in KP4 cells in the presence (WT) and absence (KO) of MYOF. shRNA-mediated knockdown of ATG3 to suppress autophagy causes a decrease in lysosome localization of CHMP1A and CHMP3 in MYOF KO cells (n = 12 fields per condition). Scale, 20μm. Data are mean ± s.d. P values determined by unpaired two-tailed Student’s t-test. Statistics source data are provided. Unmodified blots are provided in Source Data Extended Data Fig. 5. Experiment depicted in a are representative of two independent experiments.
Extended Data Fig. 6 Lysosomal targeting of MYOF delays onset of membrane damage.
a, U20S cells stably expressing T192-FLAG-FKBP and transiently transfected with MYOF-FRB* were treated with 1mM LLOMe for the indicated time points in the presence or absence of AP, followed by immunostaining for HA (green) and Galectin 3 (GAL3; red). Recruitment of MYOF-FRB* (green) protects against LLOMe induced GAL3 recruitment [n = 40 (control), 39 (15mins), 43 (30 mins), 41 (120mins) cells in the absence of AP and n = 39 (control), 45 (15mins), 41 (30mins) and 39 (120mins) cells in the presence of AP]. b, U20S cells stably expressing T192-FLAG-FKBP and transfected with MYOFΔC2-FRB* variant were treated as in ‘a’, followed by immunostaining for HA (green) and GAL3 (red). Recruitment of MYOFΔC2 (green) does not protect against LLOMe induced GAL3 recruitment [n = 26 cells per condition (-AP and +AP)]. Graphs at right show quantification of GAL3 spots per cell in response to LLOMe. Scale, 20μm for all panels. Data are mean ± s.d. P values determined by unpaired two-tailed Student’s t-tests. n.s. not significant. Statistics source data are provided.
Extended Data Fig. 7 MYOF is required for growth of mouse PDA tumours.
a, Immunoblot of the indicated proteins in mouse KPC cells (FC1245) following CRISPR-mediated knockout of Myof. b,c, Immunofluorescence staining of LC3B-positive autophagosomes in FC1245 Myof KO cells relative to Cas9 control cells. Graph shows quantification of LC3B puncta from n = 11 fields per condition. Data are mean ± s.d. d,e, Immunofluorescence images of LysoTracker red staining in FC1245 Myof KO cells compared to Cas9 control cells. Graph shows quantification from n = 70 (Cas9 control), 71 (KO#1), 70 (KO#2) cells per condition. Data are mean ± s.d. f, Growth rate of Cas9 control and Myof KO FC1245 allografts following s.c. transplantation in syngeneic C57BL/6 host mice. N=6 (Cas9 ctrl), 5 (KO#1), 5 (KO#2) animals per group. Scale, 20μm for all panels. Data represent mean ± s.e.m. P values determined by unpaired two-tailed Student’s t-tests. Statistics source data are provided. Unmodified blots are provided in Source Data Extended Data Figure 7. Experiment depicted in a are representative of two independent experiments.
Extended Data Fig. 8 DYSF expression in PDA patient samples.
DYSF transcript levels in human PDA patient specimens from 4 independent datasets as indicated. The number of samples are indicated under each graph in parentheses. Data are mean ± s.d. P values determined by unpaired two-tailed Student’s t-tests. Statistics source data are provided.
Extended Data Fig. 9 MYOF and DYSF expression in colorectal, NSCLC and breast cancer.
a,c,e, MYOF transcript levels in human colorectal cancer (CRC) (a), Non-small cell lung cancer (NSCLC) (c), and invasive breast cancer (e) patient specimens relative to normal colon, lung and breast from the indicated datasets (4 per tissue type). b,d,f, DYSF transcript levels in CRC (b), NSCLC (d), and invasive breast cancer (f) patient specimens relative to normal colon, lung and breast from the indicated datasets (as in a,c,e). Note MYOF levels are elevated in only 2 datasets while DYSF levels are elevated in 1 dataset. The number of samples are indicated under each graph in parentheses. Data are mean ± s.d. P values determined by unpaired two-tailed student’s t-tests. Statistics source data are provided.
Supplementary information
Supplementary Tables
Supplementary Table 1. Proteins identified in PDA-lysosome elutes that were >twofold significantly enriched. Supplementary Table 2. Cohort of PDA lysosomal proteins associated with vesicle trafficking and endocytosis that were >twofold significantly enriched. Supplementary Table 3. Clinicopathological characteristics and group membership in ULCA TMA (encompassing resected stage I/II pancreatic cancer). Supplementary Table 4. Cox proportional hazard models for prognostic factors. Supplementary Table 5. Antibodies used.
Source data
Source Data Fig. 1
Statistical source data
Unmodified gels Fig1
Unprocessed western blots
Source Data Fig. 2
Statistical source data
Unmodified gels Fig. 2
Unprocessed western blots
Source Data Fig. 3
Statistical source data
Unmodified gels Fig. 3
Unprocessed western blots
Source Data Fig. 4
Statistical source data
Source Data Fig. 5
Statistical source data
Unmodified gels Fig. 5
Unprocessed western blots
Source Data Fig. 6
Statistical source data
Source Data Extended Data Fig. 1
Statistical source data
Source Data Extended Data Fig. 2
Statistical source data
Unmodified gels Extended Data Fig. 2
Unprocessed western blots
Source Data Extended Data Fig. 3
Statistical source data
Unmodified gels Extended Data Fig. 3
Unprocessed western blots
Source Data Extended Data Fig. 4
Statistical source data
Unmodified gels Extended Data Fig. 4
Unprocessed western blots
Source Data Extended Data Fig. 5
Statistical source data
Unmodified gels Extended Data Fig. 5
Unprocessed western blots
Source Data Extended Data Fig. 6
Statistical source data
Source Data Extended Data Fig. 7
Statistical source data
Unmodified gels Extended Data Fig. 7
Unprocessed western blots
Source Data Extended Data Fig. 8
Statistical source data
Source Data Extended Data Fig. 9
Statistical source data
Rights and permissions
About this article
Cite this article
Gupta, S., Yano, J., Mercier, V. et al. Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth. Nat Cell Biol 23, 232–242 (2021). https://doi.org/10.1038/s41556-021-00644-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41556-021-00644-7
This article is cited by
-
Identification of myoferlin as a mitochondria-associated membranes component required for calcium signaling in PDAC cell lines
Cell Communication and Signaling (2024)
-
Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion
Nature Immunology (2024)
-
Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology
Nature Reviews Molecular Cell Biology (2024)
-
Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms
Cell Death Discovery (2023)
-
Structure and activation of the RING E3 ubiquitin ligase TRIM72 on the membrane
Nature Structural & Molecular Biology (2023)