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SUMMARY:RASA2 is a Novel Tumor Suppressor in Melanoma - Yardena Samuels\; 
 Weizmann Institute\, Israel
DTSTART:20151218T130000Z
DTEND:20151218T140000Z
UID:TALK59822@talks.cam.ac.uk
CONTACT:Neil Bennett
DESCRIPTION:Cutaneous melanoma\, for which incidence rates continue to inc
 rease\, represents a significant health problem worldwide. Recent genomic 
 studies of melanoma have discovered several driver genes and enabled devel
 opment of targeted drugs\, which show promise in treating melanoma patient
 s. However\, responses are rarely durable\; therefore there is an urgent n
 eed to identify additional targetable alterations in melanoma.  \n\nMost a
 pproved drugs that target genetically altered proteins in cancer are towar
 ds kinases. However\, a majority of the proteins mutated in cancer are tum
 or suppressors which cannot be re-activated by small molecules. A possible
  solution is exploiting the fact that tumor suppressor gene inactivation r
 esults in activation of a downstream growth pathway. We sought to systemat
 ically identify tumor suppressor genes in melanoma and characterize the do
 wnstream pathways activated by their loss of function. \n\nTo this end\, w
 e compiled and analyzed a database of 501 melanoma whole exomes\, which is
  the largest melanoma database to date to identify novel melanoma suppress
 or genes. This analysis revealed SETD2 and RASA2 as melanoma tumor suppres
 sor 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 incre
 ased RAS activation\, increasing melanoma cell growth and migration. Impor
 tantly\, RASA2 expression was lost in over 30% of human melanomas and was 
 associated with reduced patient survival. \n\nThe finding of common altera
 tions in RASA2\, together with functional data indicating its effect on ce
 ll growth and migration\, suggest that RASA2 is an important tumor suppres
 sor in human melanoma. Particularly important is the fact that RASA2 suppr
 ession provides an alternative mechanism of RAS activation. This study hig
 hlights the importance of Ras-GAPs in cancer.\n\nNotably\, as more cancer 
 genes become identified\, attention is moving towards determining their fu
 nctions. To further our understanding of our identified cancer genes in ge
 neral and RASA2 mutations in particular we are establishing several unbias
 ed proteomic methods. One of these\, which is referred to as “endogenous
  epitope tagging\,” (EET)\, makes it possible to identify the interactio
 n 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 transgene
 s\, 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 Ra
 s signaling pathway. Importantly\, the EET system has never been applied t
 o melanoma. Thus\, this approach will allow its future use to identify int
 eracting proteins of numerous mutated melanoma proteins further revealing 
 the pathways they control.\n
LOCATION:CRUK CI Lecture Theatre
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