"Transdifferentiation is the molecular underpinning of targeted therapy
resistance in gliomas"
Institution: Weill Medical College of Cornell University
Principal Investigator: Dr. Jihye Paik
Research Category: Basic Science
Glioblastoma is the most common type of brain tumor and is still incurable. The long-term goal of our study is to understand glioma pathogenesis at a molecular level in order to develop effective therapies.
Scientists examining human glioblastomas have found many mutations in a cell-surface receptor called epidermal growth factor receptor, or EGFR. These mutations cause EGFR to be much more highly activated than usual. As the name implies, EGFR has strong growth-promoting functions and has been associated with several cancers.
Unfortunately, however, drugs targeting EGFR have failed to provide survival benefits to glioblastoma patients. Our objective is to determine why these drugs are ineffective and develop strategies to overcome their limitations.
We have begun investigating this issue using human and mouse glioma cells that we know are dependent on EGFR signaling. When we reduced EGFR expression in the cells, they underwent a change in cell type, specifically a mesenchymal subtype transition. Mesenchymal cells are relatively undifferentiated and can develop into a broad range of cell types. In our EGFR-inhibited cells, we also noticed an increase in the expression of a transcription factor called SLUG, which is known to promote a mesenchymal phenotype in developing embryos. When we tried forcing SLUG expression in primary glioma cells, we indeed observed our cells transitioning to a mesenchymal state, resembling tumors in relapsing patients.
Based on these findings, we hypothesize that the source of anti-EGFR therapy resistance is the transition of glioma cells to a mesenchymal state wherein they no longer depend on EGFR signaling. Therefore, therapies should be developed that target both EGFR signaling and the subsequent emergence of mesenchymal cancerous tissue.
The above project description has been supplied by the Principal Investigator