EMT (epithelial mesenchymal transition) regulators and the crosstalk between the hypoxic and vascular tumor niche

• Applicant: Professor Dr. Till Acker
• Subject Area: Pathology
• Term: from 2006 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 21994002

The ability to initiate homeostatic responses and adapt to hypoxia represents a central aspect in solid tumor growth, crucially governed by the key transcriptional regulators hypoxia inducible transcription factor (HIF)-1a and HIF-2a. Thus, a low PO2 may via activation of the HIF system trigger the tumor cell to cover its oxygen and nutrient supply by inducing angiogenesis (angiogenic phenotype) or by migrating away from hypoxic areas into the well oxygenated host tissue and organs (invasive phenotype). Preexisting or newly formed vessels serve as migration scaffolds to support tumor spread. Interestingly, current antiangiogenic therapies seem to be counteracted by a similar switch to a more invasive phenotype that renders tumor cells independent of new blood vessel growth. We propose that such a qualitative change in the signaling response (angiogenic vs. invasive) may be governed by oxygen levels being reflected at the molecular level by HIF protein quantities (moderate vs. high). To test this hypothesis, we will analyze the distinct role and contribution of HIF-1a and/or HIF-2a and, with regard to their protein levels, the qualitative response changes in the induction of angiogenesis and (or) migration/invasion by modulating HIF-1a and HIF-2a protein levels in glioblastomas by overexpression and siRNA mediated knock-down.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1190: The Tumour-Vessel Interface