TGF-β-Induced transcription sustains amoeboid melanoma migration and dissemination
Orgaz, Jose L.
Rodríguez Hernández, Irene
Nestle, Frank O.
Karagiannis, Sophia N.
Sanz Moreno, Victoria
MetadataShow full item record
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.
Is part ofCurrent Biology, 2015, vol. 25, núm. 22, p. 2899-2914
European research projects
The following license files are associated with this item:
Showing items related by title, author, creator and subject.
Regional Activation of Myosin II in Cancer Cells Drives Tumor Progression via a Secretory Cross-Talk with the Immune Microenvironment Georgouli, Mirella; Herraiz, Cecilia; Crosas-Molist, Eva; Fanshawe, Bruce; Maiques Carlos, Oscar; Perdrix, Anna; Pandya, Pahini; Rodríguez Hernández, Irene; Ilieva, Kristina M.; Cantelli, Gaia; Karagiannis, Panagiotis; Mele, Silvia; Lam, Hoyin; Josephs, Debra H.; Matias-Guiu, Xavier; Martí Laborda, Rosa Ma.; Nestle, Frank O.; Orgaz, Jose L.; Malanchi, Ilaria; Fruhwirth, Gilbert O.; Karagiannis, Sophia N.; Sanz Moreno, Victoria (Elsevier, 2019)ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant ...
Rodriguez-Hernandez, Irene; Maiques Carlos, Oscar; Kohlhammer, Leonie; Cantelli, Gaia; Perdrix-Rosell, Anna; Monger, Joanne; Fanshawe, Bruce; Bridgeman, Victoria L.; Karagiannis, Sophia N.; Penin, Rosa M.; Marcolval, Joaquim; Martí Laborda, Rosa Ma.; Matias-Guiu, Xavier; Fruhwirth, Gilbert O.; Orgaz, Jose L.; Malanchi, Ilaria; Sanz Moreno, Victoria (Nature Research, 2020)Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels ...
Maiques Carlos, Oscar; Barceló Gómez, Carla; Panosa, Anaïs; Pijuan Marquilles, Jordi; Orgaz, Jose L.; Rodríguez Hernández, Irene; Matas Nadal, Clara; Tell, Gemma; Vilella, Ramón; Fabra, Angels; Puig, Susana; Sanz Moreno, Victoria; Matias-Guiu, Xavier; Cantí Nicolás, Carles; Herreros Danés, Judit; Martí Laborda, Rosa Ma.; Macià Armengol, Anna (Wiley, 2018)Melanoma is a malignant tumor derived from melanocytes. Once disseminated, it is usually highly resistant to chemotherapy and is associated with poor prognosis. We have recently reported that T-type calcium channels (TTCCs) ...