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1.
Physiol Rev ; 102(1): 455-510, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34541899

RESUMO

Rho GTPases are a family of small G proteins that regulate a wide array of cellular processes related to their key roles controlling the cytoskeleton. Cancer is a multistep disease caused by the accumulation of genetic mutations and epigenetic alterations, from the initial stages of cancer development when cells in normal tissues undergo transformation, to the acquisition of invasive and metastatic traits, responsible for a large number of cancer related deaths. In this review, we discuss the role of Rho GTPase signaling in cancer in every step of disease progression. Rho GTPases contribute to tumor initiation and progression, by regulating proliferation and apoptosis, but also metabolism, senescence, and cancer cell stemness. Rho GTPases play a major role in cell migration and in the metastatic process. They are also involved in interactions with the tumor microenvironment and regulate inflammation, contributing to cancer progression. After years of intensive research, we highlight the importance of relevant models in the Rho GTPase field, and we reflect on the therapeutic opportunities arising for cancer patients.


Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias/tratamento farmacológico , Microambiente Tumoral/fisiologia , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Movimento Celular/fisiologia , Transformação Celular Neoplásica/imunologia , Humanos , Transdução de Sinais/genética
2.
Nat Commun ; 11(1): 5315, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082334

RESUMO

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 of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.


Assuntos
Receptores Frizzled/metabolismo , Melanoma/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas Wnt/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Transformação Celular Neoplásica , Feminino , Receptores Frizzled/genética , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos SCID , Proteínas dos Microfilamentos/genética , Miosina Tipo II/genética , Miosina Tipo II/metabolismo , Invasividade Neoplásica , Transdução de Sinais , Proteínas Wnt/genética , Proteínas rho de Ligação ao GTP/genética , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
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