University of Cambridge > Talks.cam > Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer > RASA2 is a Novel Tumor Suppressor in Melanoma

RASA2 is a Novel Tumor Suppressor in Melanoma

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Cutaneous melanoma, for which incidence rates continue to increase, represents a significant health problem worldwide. Recent genomic studies of melanoma have discovered several driver genes and enabled development of targeted drugs, which show promise in treating melanoma patients. However, responses are rarely durable; therefore there is an urgent need to identify additional targetable alterations in melanoma.

Most approved drugs that target genetically altered proteins in cancer are towards kinases. However, a majority of the proteins mutated in cancer are tumor suppressors which cannot be re-activated by small molecules. A possible solution is exploiting the fact that tumor suppressor gene inactivation results in activation of a downstream growth pathway. We sought to systematically identify tumor suppressor genes in melanoma and characterize the downstream pathways activated by their loss of function.

To this end, we compiled and analyzed a database of 501 melanoma whole exomes, which is the largest melanoma database to date to identify novel melanoma suppressor genes. This analysis revealed SETD2 and RASA2 as melanoma tumor suppressor genes for the first time. RASA2 , encoding a RasGAP, as a novel tumor suppressor gene that is mutated in 5% of melanomas. We examined recurrent loss of function mutations in RASA2 and found that they selectively increased RAS activation, increasing melanoma cell growth and migration. Importantly, RASA2 expression was lost in over 30% of human melanomas and was associated with reduced patient survival.

The finding of common alterations in RASA2 , together with functional data indicating its effect on cell growth and migration, suggest that RASA2 is an important tumor suppressor in human melanoma. Particularly important is the fact that RASA2 suppression provides an alternative mechanism of RAS activation. This study highlights the importance of Ras-GAPs in cancer.

Notably, as more cancer genes become identified, attention is moving towards determining their functions. To further our understanding of our identified cancer genes in general and RASA2 mutations in particular we are establishing several unbiased proteomic methods. One of these, which is referred to as “endogenous epitope tagging,” (EET), makes it possible to identify the interaction partners of endogenous human proteins (i) in human cells, (ii) without requiring high quality antibodies to the individual proteins of interest, (iii) without the need for ectopic expression of epitope-tagged transgenes, and (iv) in their wild-type and mutant forms in the same cell context. These studies provide insights into the functional effects of alterations in RASA2 and identify novel cellular components that contribute to the Ras signaling pathway. Importantly, the EET system has never been applied to melanoma. Thus, this approach will allow its future use to identify interacting proteins of numerous mutated melanoma proteins further revealing the pathways they control.

This talk is part of the Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer series.

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