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Project description:Cancer genetics has uncovered many tumor-suppressor and oncogenic pathways, but few alterations have revealed mechanisms involved in tumor spreading. Here, we examined the role of the third most significant chromosomal deletion in human melanoma that inactivates the adherens junction gene NECTIN1 in 55% of cases. We found that NECTIN1 loss stimulates melanoma cell migration in vitro and spreading in vivo in both zebrafish and human tumors specifically in response to decreased IGF1 signaling. In human melanoma biopsy specimens, adherens junctions were seen exclusively in areas with low IGF1 levels, but not in NECTIN1-deficient tumors. Our study establishes NECTIN1 as a major determinant of melanoma dissemination and uncovers a genetic control of the response to microenvironmental signals.
| S-EPMC9729115 | biostudies-literature
Project description: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.
2022-05-26 | GSE174149 | GEO
Project description:Frequent loss of adhesion gene NECTIN1 triggers melanoma dissemination upon local IGF1 depletion
| PRJNA728590 | ENA
Project description:Frequent loss of adhesion gene NECTIN1 triggers melanoma dissemination upon local IGF1 depletion [RNA-Seq]
| PRJNA728593 | ENA
Project description:Defects in cell-cell contacts have been proposed to participate in early steps of tumor metastasis1 but little is known about the signals from the cancer cell niche that influence this process. Here, we show that the lack of adherens junctions caused by genetic loss of the adhesion molecule NECTIN1 in melanoma promotes tumor dissemination specifically under growth factor deprivation. We found that NECTIN1 was deleted in 53% of human melanomas and that its loss was enriched in metastases. NECTIN1 inactivation in zebrafish melanomas stimulated cancer cell spreading in vivo, while in human cell lines, it increased cell migration specifically in response to serum starvation. We further identified IGF1 as the serum component responsible for this effect. Serum withdrawal or IGF1 inhibition induced formation of strong adherens junctions between NECTIN1-wild-type melanoma cells. In contrast, NECTIN1-deficient cells were unable to establish adherens junctions and instead activated integrin-mediated motility through a FAK/SRC axis. During melanoma dissemination, NECTIN1 loss thus causes a cellular phenotypic switch from cell-cell adhesion to cell-matrix adhesion triggered by IGF1 signaling. Our study uncovers a mechanism by which cancer cells integrate information from the tumor microenvironment and cell-cell contacts to regulate their migratory behavior during spreading.
2022-05-26 | GSE149481 | GEO
Project description:Apoptosis is an important antivirus defense by virtue of its impact on virus multiplication and pathogenesis. To define molecular mechanisms by which viruses are detected and the apoptotic response is initiated, we examined the antiviral role of host inhibitor-of-apoptosis (IAP) proteins in insect cells. We report here that the principal IAPs, DIAP1 and SfIAP, of the model insects Drosophila melanogaster and Spodoptera frugiperda, respectively, are rapidly depleted and thereby inactivated upon infection with the apoptosis-inducing baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV). Virus-induced loss of these host IAPs triggered caspase activation and apoptotic death. Elevation of IAP levels by ectopic expression repressed caspase activation. Loss of host IAP in both species was triggered by AcMNPV DNA replication. By using selected inhibitors, we found that virus-induced IAP depletion was mediated in part by the proteasome but not by caspase cleavage. Consistent with this conclusion, mutagenic disruption of the SfIAP RING motif, which acts as an E3 ubiquitin ligase, stabilized SfIAP during infection. Importantly, SfIAP was also stabilized upon the removal of its 99-residue N-terminal leader, which serves as a critical determinant of IAP turnover. These data indicated that a host pathway initiated by virus DNA replication and acting through instability motifs embedded within IAP triggers IAP depletion and thereby causes apoptosis. Taken together, the results of our study suggest that host modulation of cellular IAP levels is a conserved mechanism by which insects mount an apoptotic antiviral response. Thus, host IAPs may function as critical sentinels of virus invasion in insects.
| S-EPMC3147993 | biostudies-literature
Project description:Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], a phosphoinositide concentrated predominantly in the plasma membrane, binds endocytic clathrin adaptors, many of their accessory factors, and a variety of actin-regulatory proteins. Here we have used fluorescent fusion proteins and total internal reflection fluorescence microscopy to investigate the effect of acute PI(4,5)P(2) breakdown on the dynamics of endocytic clathrin-coated pit components and of the actin regulatory complex, Arp2/3. PI(4,5)P(2) breakdown was achieved by the inducible recruitment to the plasma membrane of an inositol 5-phosphatase module through the rapamycin/FRB/FKBP system or by treatment with ionomycin. PI(4,5)P(2) depletion resulted in a dramatic loss of clathrin puncta, which correlated with a massive dissociation of endocytic adaptors from the plasma membrane. Remaining clathrin spots at the cell surface had only weak fluorescence and were static over time. Dynamin and the p20 subunit of the Arp2/3 actin regulatory complex, which were concentrated at late-stage clathrin-coated pits and in lamellipodia, also dissociated from the plasma membrane, and these changes correlated with an arrest of motility at the cell edge. These findings demonstrate the critical importance of PI(4,5)P(2) in clathrin coat dynamics and Arp2/3-dependent actin regulation.
| S-EPMC1805489 | biostudies-literature
Project description:NECTIN1 controls an IGF1-dependent adhesion switch in melanoma spreading
| PRJNA628861 | ENA
Project description:Loss of expression of the cell-cell adhesion molecule E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) in development and in the progression from epithelial tumours to invasive and metastatic cancers. Here, we demonstrate that the loss of E-cadherin function upregulates expression of the neuronal cell adhesion molecule (NCAM). Subsequently, a subset of NCAM translocates from fibroblast growth factor receptor (FGFR) complexes outside lipid rafts into lipid rafts where it stimulates the non-receptor tyrosine kinase p59(Fyn) leading to the phosphorylation and activation of focal adhesion kinase and the assembly of integrin-mediated focal adhesions. Ablation of NCAM expression during EMT inhibits focal adhesion assembly, cell spreading and EMT. Conversely, forced expression of NCAM induces epithelial cell delamination and migration, and high NCAM expression correlates with tumour invasion. These results establish a mechanistic link between the loss of E-cadherin expression, NCAM function, focal adhesion assembly and cell migration and invasion.
| S-EPMC2567408 | biostudies-literature
Project description:BACKGROUND: Cancer/testis (CT) genes are expressed only in the germ line and certain tumors and are most frequently located on the X-chromosome (the CT-X genes). Amongst the best studied CT-X genes are those encoding several MAGE protein families. The function of MAGE proteins is not well understood, but several have been shown to potentially influence the tumorigenic phenotype. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a mutational analysis of coding regions of four CT-X MAGE genes, MAGEA1, MAGEA4, MAGEC1, MAGEC2 and the ubiquitously expressed MAGEE1 in human melanoma samples. We first examined cell lines established from tumors and matching blood samples from 27 melanoma patients. We found that melanoma cell lines from 37% of patients contained at least one mutated MAGE gene. The frequency of mutations in the coding regions of individual MAGE genes varied from 3.7% for MAGEA1 and MAGEA4 to 14.8% for MAGEC2. We also examined 111 fresh melanoma samples collected from 86 patients. In this case, samples from 32% of the patients exhibited mutations in one or more MAGE genes with the frequency of mutations in individual MAGE genes ranging from 6% in MAGEA1 to 16% in MAGEC1. SIGNIFICANCE: These results demonstrate for the first time that the MAGE gene family is frequently mutated in melanoma.
| S-EPMC2940856 | biostudies-literature