Integrins are a large family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions.,Among the 24 integrin isoforms, many have been found to be associated with tumor angiogenesis, tumor cell migration and proliferation, and metastasis.,Integrins, especially αvβ3, αvβ5 and α5β1, participate in mediating tumor angiogenesis by interacting with the vascular endothelial growth factor and angiopoietin-Tie signaling pathways.,Melanoma patients have a poor prognosis when the primary tumor has generated distant metastases, and the melanoma metastatic site is an independent predictor of the survival of these patients.,Different integrins on the melanoma cell surface preferentially direct circulating melanoma cells to different organs and promote the development of metastases at specific organ sites.,For instance, melanoma cells expressing integrin β3 tend to metastasize to the lungs, whereas those expressing integrin β1 preferentially generate lymph node metastases.,Moreover, tumor cell-derived exosomes which contain different integrins may prepare a pre-metastatic niche in specific organs and promote organ-specific metastases.,Because of the important role that integrins play in tumor angiogenesis and metastasis, they have become promising targets for the treatment of advanced cancer.,In this paper, we review the integrin isoforms responsible for angiogenesis and organ-specific metastasis in malignant melanoma and the inhibitors that have been considered for the future treatment of metastatic disease.
Cell migration underlies metastatic dissemination of cancer cells, and fast “amoeboid” migration in the invasive fronts of tumors is controlled by high levels of actomyosin contractility.,How amoeboid migration is regulated by extracellular signals and sustained over time by transcriptional changes is not fully understood.,Transforming growth factor β (TGF-β) is well known to promote epithelial-to-mesenchymal transition (EMT) and contribute to metastasis, but melanocytes are neural crest derivatives that have undergone EMT during embryonic development.,Surprisingly, we find that in melanoma, TGF-β promotes amoeboid features such as cell rounding, membrane blebbing, high levels of contractility, and increased invasion.,Using genome-wide transcriptomics, we find that amoeboid melanoma cells are enriched in a TGF-β-driven signature.,We observe that downstream of TGF-β, SMAD2 and its adaptor CITED1 control amoeboid behavior by regulating the expression of key genes that activate contractile forces.,Moreover, CITED1 is highly upregulated during melanoma progression, and its high expression is associated with poor prognosis.,CITED1 is coupled to a contractile-rounded, amoeboid phenotype in a panel of 16 melanoma cell lines, in mouse melanoma xenografts, and in 47 human melanoma patients.,Its expression is also enriched in the invasive fronts of lesions.,Functionally, we show how the TGF-β-SMAD2-CITED1 axis promotes different steps associated with progression: melanoma detachment from keratinocytes, 2D and 3D migration, attachment to endothelial cells, and in vivo lung metastatic initial colonization and outgrowth.,We propose a novel mechanism by which TGF-β-induced transcription sustains actomyosin force in melanoma cells and thereby promotes melanoma progression independently of EMT.,•TGF-β-SMAD promotes amoeboid migration in melanoma•Downstream of TGF-β, the adaptor CITED1 controls actomyosin contractility•Amoeboid features correlate with CITED1 levels in cell lines, xenografts, and patients•TGF-β-SMAD-CITED1 transcriptional network controls melanoma metastatic ability,TGF-β-SMAD promotes amoeboid migration in melanoma,Downstream of TGF-β, the adaptor CITED1 controls actomyosin contractility,Amoeboid features correlate with CITED1 levels in cell lines, xenografts, and patients,TGF-β-SMAD-CITED1 transcriptional network controls melanoma metastatic ability,Cantelli et al. find that, in melanoma, TGF-β-SMAD-CITED1 controls amoeboid behavior through activation of a transcriptional program.,As a result, melanoma cells detach from keratinocytes, increase their invasive potential, and efficiently colonize the lung.,This is a new function of TGF-β, independent of epithelial-to-mesenchymal transition.