Host institution: Technion, Israel Institute of Technology; Haifa, Israel
PI: Eyal Gottlieb.
Aim and Background: Cancer cells have increased bioenergetic demands and proliferation rates, and have defense mechanisms that are selected for under conditions of stress. Identifying and targeting these survival mechanisms may help eliminate cancer growth and specifically induce cancer cell death. Since hypoxia is not common in normal tissues, genes that are specifically essential for the survival of hypoxic cells can be considered potential targets for preferentially killing cancer cells. We aim to identify specific vulnerabilities cancer cells under hypoxia. Research: We will study triple negative breast cancer (TNBC) cell lines as this breast tumor subtype is very difficult to treat and associated with poor patient outcome. The research will combine several comprehensive approaches. We will conduct transcriptomic (RNA-Seq) analyses to identify genes that are up-regulated in hypoxic conditions focusing on metabolic genes (enzymes and metabolite transporters). These results will be integrated with data from primary tumours using systems biology and network analysis to try and model a metabolic gene profile with hypoxic signatures, stage of the disease and prognosis. Candidate genes that are potentially essential for hypoxia survival will be tested in vitroutilising RNAi and CRISPR technologies. This will be followed by tumor xenograft animal models utilizing inducible shRNA systems. Outputs: i) identification of enzymes and metabolite transporters modulated upon hypoxia, ii) model a metabolic gene profile, iii) list of potential new targets for validation studies.