AbstractMelanoma is the most deadly form of skin cancer, accounting for over 10000 yearly deaths worldwide. During progression, melanoma cells detach from the surrounding epithelium and invade into the underlying dermis, entering blood vessels and disseminating throughout the body and to form metastases. Invading melanoma cells switch between different modes of migration, namely the adhesion-dependent “elongated-mesenchymal” mode and the highly invasive “rounded-amoeboid” mode. Amoeboid motility relies on RhoA/ROCK driven actomyosin contractility and can be driven by several chemical and physical stimuli, such as MMP9, IL-6 or confinement. Melanoma cells are thought to transition from the former to the latter throughout progression in what is known as the mesenchymal-to-amoeboid transition (MAT).
The work presented in this thesis identifies TGFβ as a driver of MAT. In particular, it shows that SMAD2/CITED1 driven transcription is necessary to activate actomyosin contractility and therefore sustain amoeboid behaviour. Moreover, CITED1- driven transcription is necessary for melanoma cell detachment from keratinocytes, invasion through collagen, dissemination and formation of metastatic lesions in the lung. The TGFβ-dependent transcription factor SMAD2 is shown to be directly phosphoactivated by ROCK, resulting in increased TGFβ-driven transcription. Therefore, Rho/ROCK driven actomyosin contractility can feed back to TGFβ signalling in a positive feedback loop sustaining amoeboid motility. Furthermore, the work presented here shows how the transcriptional programme underlying MAT is the result of a hyperactivation of an EMT program. This is especially interesting as melanoma cells are neural crest derivatives and as such they have already undergone EMT during development. As part of a hyper-activated EMT signature, non-canonical WNT also appears to drive MAT in melanoma cells.
In conclusion, this thesis finds that actomyosin contractility in melanoma cells is controlled by a complex network of transcriptional signals, orchestrated by extracellular stimuli such as TGFβ and non-canonical WNT.
|Date of Award
|Vicky Sanz Moreno (Supervisor) & Anne Ridley (Supervisor)