RAS AND MMP7

Investigation of a dependency of RAS-driven cancers on matrix metalloproteinase-7

Coordinatore	CANCER RESEARCH UK    more  Organization address address: ST JOHN STREET 407 ANGEL BUILDING city: LONDON postcode: EC1V 4AD contact info Titolo: Ms. Nome: Holly Cognome: Elphinstone Email: send email Telefono: +44 20 7269 3524 Fax: +44 20 7269 3585
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	172˙740 €
EC contributo	172˙740 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2009-IEF
Funding Scheme	MC-IEF
Anno di inizio	2011
Periodo (anno-mese-giorno)	2011-01-01   -   2012-12-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	CANCER RESEARCH UK  Organization address address: ST JOHN STREET 407 ANGEL BUILDING city: LONDON postcode: EC1V 4AD contact info Titolo: Ms. Nome: Holly Cognome: Elphinstone Email: send email Telefono: +44 20 7269 3524 Fax: +44 20 7269 3585	UK (LONDON)	coordinator	172˙740.80

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 Obiettivo del progetto (Objective)

'Activating point mutations in RAS are present in a large number of tumours. Besides treating tumours by reversing the effects of oncoproteins through inhibition, another approach is to use therapies that target tumour-specific vulnerabilities caused by the oncogenic state. To investigate this possibility, an siRNA screen has been performed in order to identify new genes necessary for the RAS-driven oncogenic state. This approach has led to the identification of the matrix metalloproteinase-7 (MMP-7) as a protein required for the survival of cells with an activated KRAS allele. MMP-7 is a member of the matrix metalloproteinase family that has broad substrate selectivity against extracellular matrix components and some non-matrix substrates. MMP-7 is overexpressed in a variety of tumours and is associated with unfavourable prognosis. The main aim of this project is to study the mechanism underlying the dependency of cells with RAS activating mutations on MMP-7 expression. To determine this we will study four different pathways. MMP-7 can suppress apoptotic FasL/Fas pathway by cleaving FasL and reducing its efficacy in triggering Fas signals. Alternatively, MMP-7, by cleaving E-cadherin, can increase β-catenin-Wnt pathway, which is required by several tumour types. Moreover, MMP-7 proteolysis of IGFBP-3 plays a crucial role in regulating IGF-I bioavailability, thereby promoting cell survival. Finally, MMP-7 can process HB-EGF that will activate ErB4 signalling. This leads to a survival signalling through receptor tyrosine kinases. We will also study MMP-7 dependency in vivo using MMP-7 knock-out mice crossed with a RAS mutated mouse model. Results obtained may lead to improved cancer therapies, with the possibility that certain tumour types with high levels of RAS mutations could be treated with specific MMP-7 inhibitors. Moreover, identification of the mechanism of MMP-7 dependence will also allow the identification of new pharmacological targets.'