Peripheral positioning of lysosomes supports melanoma aggressiveness

Katerina Jerabkova-Roda (), Marina Peralta, Kuang-Jing Huang, Antoine Mousson, Clara Bourgeat Maudru, Louis Bochler, Ignacio Busnelli, Rabia Karali, Hélène Justiniano, Lucian-Mihai Lisii, Philippe Carl, Vincent Mittelheisser, Nandini Asokan, Annabel Larnicol, Olivier Lefebvre, Hugo Lachuer, Angélique Pichot, Tristan Stemmelen, Anne Molitor, Léa Scheid, Quentin Frenger, Frédéric Gros, Aurélie Hirschler, François Delalande, Emilie Sick, Raphaël Carapito, Christine Carapito, Dan Lipsker, Kristine Schauer (), Philippe Rondé (), Vincent Hyenne () and Jacky G. Goetz ()
Additional contact information
Katerina Jerabkova-Roda: Tumor Biomechanics
Marina Peralta: Tumor Biomechanics
Kuang-Jing Huang: Tumor Biomechanics
Antoine Mousson: Université de Strasbourg
Clara Bourgeat Maudru: Tumor Biomechanics
Louis Bochler: Tumor Biomechanics
Ignacio Busnelli: Tumor Biomechanics
Rabia Karali: Université de Strasbourg
Hélène Justiniano: Université de Strasbourg
Lucian-Mihai Lisii: Université de Strasbourg
Philippe Carl: Université de Strasbourg
Vincent Mittelheisser: Tumor Biomechanics
Nandini Asokan: Tumor Biomechanics
Annabel Larnicol: Tumor Biomechanics
Olivier Lefebvre: Tumor Biomechanics
Hugo Lachuer: CNRS
Angélique Pichot: INSERM UMR_S1109
Tristan Stemmelen: INSERM UMR_S1109
Anne Molitor: INSERM UMR_S1109
Léa Scheid: Hôpitaux Universitaires de Strasbourg
Quentin Frenger: INSERM UMR_S1109
Frédéric Gros: INSERM UMR_S1109
Aurélie Hirschler: Infrastructure Nationale de Protéomique ProFI
François Delalande: Infrastructure Nationale de Protéomique ProFI
Emilie Sick: Université de Strasbourg
Raphaël Carapito: INSERM UMR_S1109
Christine Carapito: Infrastructure Nationale de Protéomique ProFI
Dan Lipsker: Hôpitaux Universitaires de Strasbourg
Kristine Schauer: CNRS
Philippe Rondé: Université de Strasbourg
Vincent Hyenne: Tumor Biomechanics
Jacky G. Goetz: Tumor Biomechanics

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58528-5

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