Peripheral positioning of lysosomes supports melanoma aggressiveness

K. Jerabkova-Roda (1, 2, 3) , A. Mousson (2, 4, 1, 5) , M. Peralta (1, 2, 3) , R. Karali (2, 4, 1, 5) , H. Justiniano (2, 4, 1, 5) , L.M. Lisii (2, 4, 1, 5) , P. Carl (2, 4, 1, 5) , N. Asokan (1, 2, 3) , I. Busnelli (1, 2, 3) , A. Larnicol (1, 2, 3) , O. Lefebvre (1, 2, 3) , H. Lachuer (6) , A. Pichot (2, 4, 1, 5) , T. Stemmelen (2, 4, 1, 5) , A. Molitor (2, 4, 1, 5) , A. Hirschler (7) , F. Delalande (7) , E. Sick (2, 4, 1, 5) , R. Carapito (2, 4, 1, 5) , C. Carapito (8, 9) , V. Hyenne (1, 2, 3) , Kristine Schauer (10, 11) , P. Rondé (4) , J.G. Goetz (1, 2)

1 IRM - Immuno-Rhumatologie Moléculaire
2 UNISTRA - Université de Strasbourg
3 CNRS SNC5055
4 LBP - Laboratoire de Bioimagerie et Pathologies
5 IBMP - Institut de Biologie Moléculaire des Plantes
6 Biologie Cellulaire et Cancer
7 LSMBO - Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg]
8 FR ProFI - Fédération de Recherche nationale ProFI
9 DSA-IPHC - Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires
10 TCD - Dynamique des cellules tumorales
11 IGR - Institut Gustave Roussy

Emerging evidences suggest that both 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 the function of lysosomes is linked to their position and how this controls metastatic progression remains elusive. Here, we analyzed lysosome subcellular distribution in micropatterned patient-derived melanoma cells and found that lysosome spreading scales with their aggressiveness. Peripheral lysosomes promote invadopodia-based matrix degradation and invasion of melanoma cells which is directly linked to their lysosomal and cell transcriptional programs. When controlling lysosomal positioning using chemo-genetical heterodimerization in melanoma cells, we demonstrated that perinuclear clustering impairs lysosomal secretion, matrix degradation and invasion. Impairing lysosomal spreading in a zebrafish metastasis model significantly reduces invasive outgrowth. Our study provides a mechanistic demonstration that lysosomal positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis.

Mots clés: Lysosome; Invasion; Metastasis; Lysosome

Domaines: Sciences du Vivant [q-bio]

K. Jerabkova-Roda, A. Mousson, M. Peralta, R. Karali, H. Justiniano, et al.. Peripheral positioning of lysosomes supports melanoma aggressiveness. 2023. ⟨hal-04308597⟩