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Molecular mechanisms of melanoma invasion

Final Report Summary - MELANOMA INVASION (Molecular mechanisms of melanoma invasion)

Melanoma is a malignant proliferation of the pigment cells of the skin i.e. melanocytes. Its incidence has dramatically increased in the last 50 years. About 160,000 new cases of melanoma are diagnosed and 48,000 melanoma related death occur worldwide each year. Skin melanoma like most cancer is a multistep process in which cells proliferate in an uncontrolled fashion, invade the surrounding tissue and eventually migrate to secondary organs to form metastasis. Although melanoma can be surgically removed if detected early, metastatic melanoma is generally unresectable and refractory to most therapies and hence has a very poor prognosis. There is therefore an urgent need for understanding the molecular mechanisms that drive cancer cell invasion and metastasis.
Dys-regulation of cell migration is a key event in invasion and metastasis. Tumour cells may move in collective groups or as individual cells. Individually moving tumour cells do not use a single universal mechanism of cell movement but can move in either an elongated mesenchymal mode of migration or in rounded, “amoeboid” modes that are dependent on high levels of actomyosin contractility (Friedl and Wolf 2010). Interestingly, cancer cells can switch from one morphology to the other depending on the surrounding environment, a process referred to as tumour cell morphological plasticity.
Little is known about the molecular mechanism that regulates morphological plasticity. This work has generated new information about regulation of tumour cell shape change and provided a new set of targets for the development of drugs for melanoma skin cancer.
Using an unbiased approach based on RNAi screen against all the kinases and phosphatases in Drosophila cells, our main collaborator Dr. Chris Bakal has characterised the number of shapes a cell can undergo and to determined genes that define cellular shapes. He’s shown that cells can adopt 5 distinct shapes and that knock down of genes does not create new shapes but rather enrich for particular shape(s). We then validated the most significant hits in human melanoma cells both in vitro and in vivo. As we know that melanoma cells switch between round and elongated shapes we’ve selected genes the knock down of which enriched for elongated shape. As an example we have shown that the tumour suppressor phosphatase and tensin homologue PTEN is a key regulator of melanoma cells morphology both, in vitro using invasion in collagen-I gel and in vivo using an orthotopic mouse model for melanoma. We show that loss of PTEN not only increases the proportion of elongated melanoma cells but also impacts on transitioning between shapes. This finding is particularly relevant in a translational context as we are now in the process of determining genes the inhibition of which will impair morphological plasticity and therefore will reduce the aptitude of tumour cells to adapt to the change in their environment during the metastasis process eventually leading to a decrease in metastasis. This work has been recently published in Nature Cell Biology.
A second aspect of the work related to development of drugs that inhibits both type of movement of melanoma in vitro and in vivo. We have established that Rho kinase-driven actomyosin contractility is needed for both types of movement. In collaboration with pharmaceutical companies we have characterised new compounds that showed strong potency toward inhibition of the kinase ROCK in vitro and in cells. We have shown that these compounds inhibits all type of movement during invasion irrespectively of the genetic background of the melanoma cell we’ve tested (n=12). We also showed that these compounds strongly inhibit melanoma metastasis to the lungs after orthotopic injection in mice. This is the first study that shows that Rho kinase potent inhibition impairs spontaneous melanoma metastasis. A manuscript reporting results from this part is in preparation.
In conclusion this work has achieved its main objectives by determining new regulators of melanoma shape/movement paving the way for the development of new drugs for skin melanoma.
Metastatic melanoma kills 2,200 persons per year in the UK as the disease is refractory to most treatments, the new compounds we’ve developed not only will provide a new alternative for targeted therapies in melanoma but also will benefit to more patients than the classical therapies.

Friedl, P. and K. Wolf (2010). "Plasticity of cell migration: a multiscale tuning model." J Cell Biol 188(1): 11-19.