EMT (epithelial mesenchymal transition) regulators and the crosstalk between the hypoxic and vascular tumor niche
Final Report Abstract
Glioblastoma (GBM) is the most frequent primary brain tumor in adults, with a very aggressive course and few therapeutic options. Hypoxia is a typical feature of GBM and other malignant tumors, which frequently outpace their blood supply, and it is associated with poor patient prognosis. Work over the past decade has shown that the hypoxic microenvironment drives tumor progression by triggering a set of adaptive transcriptional responses. These cellular responses are primarily controlled by the transcription factor system of the hypoxia-inducible factors (HIFs). One of the key responses elicited by hypoxia/HIF is the induction of angiogenesis, in order to restore the tumor’s oxygen supply. It has further become clear that tumor hypoxia and the tumor vasculature also generate specific microenvironments that control various aspects of cancer progression. The understanding of the mechanisms regulating the formation and the function of the hypoxic and vascular microenvironments in tumor progression has formed the focus of our research project. A variety of tumors are now believed to originate from and be maintained by cells with stem cell character, termed cancer stem cells (CSCs). Thus, CSCs represent critical therapeutic targets, however, the molecular mechanisms that regulate CSCs remain poorly understood. Our studies highlight the function of specialized microenvironments (niches) in the control of CSCs. We demonstrate that blood vessels and hypoxia create important microenvironments, in which CSCs reside and are functionally maintained by specific signals. The hypoxic niche controls CSC maintenance, primarily through activation of HIF-2. Additionally, we identify EphrinB2 as an important regulator of the vascular niche, that directs angiogenic sprouting through the regulation of VEGFR tracking and signaling. Lastly, our studies identify HIF as an important regulator of a repertoire of EMT factors including SNAIL and ZEB. EMT (epithelial mesenchymal transition) has been described as a cell-biological program that is required for the acquisition of a malignant phenotype in epithelial tumors promoting tumor invasion and metastasis. Our own results indicate that individual EMT factor families regulate diverse aspects of tumor progression such as invasive/migratory features, mesenchymal differentiation as well as self-renewal and stem cell capacities. Importantly, EMT regulated mechanisms may evoke tumor resistance towards current therapeutic strategies such as anti-angiogenesis. Collectively, our findings establish the promotion of the CSC and EMT phenotype by microenvironmental cues such as hypoxia or blood vessel derived signals as an additional, possibly key mechanism through which hypoxia regulates tumor growth and progression. A more detailed understanding of the niche specific control of these phenotypes may not only provide further information on essential tumor biology processes such as invasion, metastasis and self renewal but may give crucial hints on how to avoid and counter tumor-induced evasive strategies that outmaneuver current therapeutic approaches.
