RAS AND MMP7 · Investigation of a dependency of RAS-driven cancers on matrix metalloproteinase-7

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.