Peripheral positioning of lysosomes supports melanoma aggressiveness
Résumé
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.
Metastases are responsible for the majority of cancer-related deaths 1 . Melanoma shows strong negative correlation between cancer stage and 5-year patient survival, making it an ideal model to study phenotypic changes leading to cancer cell invasion, adaptation and survival. Melanoma progression consists of multiple sequential events and its early detection is key for patient survival. First, melanocytes are transformed and grow in the epidermis during radial growth phase (RGP), forming a lesion with low potential to develop metastasis. Changes in their transcription program lead to expression of matrixdegrading enzymes and to invasion through the dermis during vertical growth phase (VGP) followed by cancer dissemination through vascular and lymphatic routes, progressing into metastatic stages 2 .
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