Peripheral positioning of lysosomes supports melanoma aggressiveness

Emerging evidence suggests that the function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how their function is linked to their position and how this controls metastasis remains elusive. Here, we analyze lysosome subcellular distribution in patient-derived melanoma cells and patient biopsies and show that lysosome spreading scales with melanoma aggressiveness. Peripheral lysosomes promote matrix degradation and cell invasion which is directly linked to the lysosomal and cell transcriptional programs. Using chemo-genetical control of lysosome positioning, we demonstrate that perinuclear clustering impairs lysosome secretion, matrix degradation and invasion. Impairing lysosome spreading significantly reduces invasive outgrowth in two in vivo models, mouse and zebrafish. Our study provides a direct demonstration that lysosome positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis and suggesting its potential utility for diagnosis of metastatic melanoma.

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Publication Details

Journal
Nature Communications
Published
2025-04-09
DOI
https://doi.org/10.1038/s41467-025-58528-5
Citations
14
Primary Topic
Cellular transport and secretion
Type
article
Field-Weighted Citation Impact
16.12

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article

Peripheral positioning of lysosomes supports melanoma aggressiveness

Émilie Sick, Annabel Larnicol, Jacky G. Goetz, Kateřina Jeřábková et al.
14 citations
Nature Communications
Cellular transport and secretion
16.12
article

Peripheral positioning of lysosomes supports melanoma aggressiveness

Émilie Sick, Annabel Larnicol, Jacky G. Goetz, Kateřina Jeřábková, Vincent Mittelheisser, Hugo Lachuer, Dan Lipsker, Tristan Stemmelen, François Delalande, Philippe Carl, Olivier Lefèbvre, Angélique Pichot, Aurélie Hirschler, Ignacio Busnelli, Hélène Justiniano, Marina Peralta, Kristine Schauer, Frédéric Gros, Raphaël Carapito, Quentin Frenger, Kuang-Jing Huang, Anne Molitor, Philippe Rondé, Christine Carapito, Nandini Asokan, Vincent Hyenne, Antoine Mousson, Rabia Karali, Lucian-Mihai Lisii, Louis Bochler, Léa Scheid, Clara Bourgeat Maudru
article en
14 citations

Abstract

Emerging evidence suggests that the function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how their function is linked to their position and how this controls metastasis remains elusive. Here, we analyze lysosome subcellular distribution in patient-derived melanoma cells and patient biopsies and show that lysosome spreading scales with melanoma aggressiveness. Peripheral lysosomes promote matrix degradation and cell invasion which is directly linked to the lysosomal and cell transcriptional programs. Using chemo-genetical control of lysosome positioning, we demonstrate that perinuclear clustering impairs lysosome secretion, matrix degradation and invasion. Impairing lysosome spreading significantly reduces invasive outgrowth in two in vivo models, mouse and zebrafish. Our study provides a direct demonstration that lysosome positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis and suggesting its potential utility for diagnosis of metastatic melanoma.

Nature CommunicationsVol. 16(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Regenerative NanoMedicine (FR), Laboratoire de Biophotonique et Pharmacologie (FR), La Ligue Contre le Cancer (FR), Biomechanics Institute of Valencia (ES), European Molecular Biology Laboratory (IT), Institut Jacques Monod (FR), Hôpitaux Universitaires de Strasbourg (FR), Biologie cellulaire et Cancer (FR), Université de Strasbourg (FR), Institut Curie (FR)
Infrastructures en Biologie Santé et Agronomie, Alliance Nationale pour les Sciences de la Vie et de la Santé, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Université de Strasbourg, Ligue Contre le Cancer, Institut National Du Cancer, Servier, National Science and Technology Council
Zero hunger
Openalex Percentile: Top 1%
Cellular transport and secretion
16.12
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