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Frequent loss of adhesion gene NECTIN1 triggers melanoma dissemination upon local IGF1 depletion [RNA-Seq]

ABSTRACT: Defects in cell-cell contacts participate in early steps of tumor metastasis, but the mechanism regulating the staying-at-home or leaving decision has not been molecularly defined. We found the adherens junction gene NECTIN1 deleted in 55% of human melanomas. Inactivation of NECTIN1 stimulated cancer cell spreading in zebrafish melanomas in vivo, and increased cell migration in human cell lines specifically in response to decreased IGF1 signaling. IGF1 inhibition induced robust formation of adherens junctions between NECTIN1-wildtype melanoma cells, while NECTIN1-deficient cells were unable to establish these junctions and instead activated integrin/FAK-mediated motility. In 20 human melanoma biopsies, adherens junctions were seen exclusively in areas with low IGF1 levels, but not in NECTIN1-deficient tumors. Our study uncovers a mechanism by which the status of cell-cell contacts modulates the cellular response to microenvironmental signals, effecting a decision switch between leaving and staying in the cancer cell niche.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174149 | GEO | 2022/05/26

REPOSITORIES: GEO

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Project description:The poor prognosis of diffuse gliomas is the consequence of adaptive growth and survival programs coupled to their unsurmountable capacity to infiltrate the brain. Diffuse brain infiltration is a particularly detrimental hallmark of gliomas, however the underlying cellular and signaling mechanisms remain elusive. Histological analysis of glioma samples suggests brain invasion by individual glioma cells extending along blood vessels and nerve tracts, consistent with individual-cell growth and invasion programs. However, using thick 3D tissue sections, we here show that human diffuse gliomas consist of multicellular networks in both tumor center and invasion region. This was confirmed in three orthotopic human glioma xenograft models in mouse brain reflecting neuronal, proneural and mesenchymal subtypes. The connections between glioma cells are provided by either branched filamentous protrusions connecting cells across distance or epithelial-like linear adherens junctions between directly adjacent cells. These intercellular contacts showed dynamic turn-over kinetics, which enabled intercellularly synchronized calcium signaling waves, directionally persistent migration as network and network plasticity. Interference with the stability of adherens junction by downregulating p120-catenin causes irreversibly compromised cell-cell interaction, near-complete inhibition of diffuse brain infiltration and a severe growth defect and marginalized microlesions as outcome. Mining of human glioma cohorts revealed an inverse association of p120 with patient survival and, using next-generation RNA sequencing, profound cell reprogramming with perturbed cell adhesion and axonal guidance pathways was uncovered after p120 downregulation. In conclusion, reminiscent of neuronal and glial progenitor programs during morphogenesis and repair, diffuse gliomas progress as neuronal-like, collective network the subunits of which cooperate by complex cell-cell signaling to promote cell growth and detrimental brain infiltration. Targeting adherens junctions and cell-cell cooperation thus represent unanticipated therapeutic principles to prevent glioma progression.

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Frequent loss of adhesion gene NECTIN1 triggers melanoma dissemination upon local IGF1 depletion [RNA-Seq]

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