Career Development Program
Project Seven: The role of Twist1 in invasion of head and neck squamous cell carcinoma
Theodora Danciu, D.M.D., D.M.Sc.
Specific Aims are:
The transition of a dysplastic epithelial lesion to an invasive squamous cell carcinorna necessitates malignant cells to acquire the ability to perforate the underlying basement membrane and migrate through connective tissue. Numerous studies suggest that the induction of an invasive phenotype is linked to the expression of transcription factors capable of promoting an epithelial- mesenchymal cell transition (EMT). a process by which epitheiial cells lose their potarity and adopt a mesenchymal morphoiogy. A key protein regulating this process is the basic helix-loop-helix transcription factor Twist1, whose activity is modulated by Akt phosphoryiation- No studies have addressed whether, or how. Twist1 phosphorylation contributes to EMT programs in cancer. Due to its association with invasion, early steps of metastasis, and drug resistance, inhibition of EMT appears to be a viable strategy for novel approaches for cancer therapy. In addition to its potential role in treatment, EMT status may be used as a biomarker for patient selection as it can indicate insensitivity to chemotherapeutic drugs- Our hypothesis is that Twist1 contributes to Head and neck squamous cell carcinoma (HNSCC) developrnent and invasion by promoting EMT, and that the EMT- related activity of this transcription factor is modified through Akt phosphorylation. interactions between carcinoma cells and the underlying basement membrane at the primary tumor site constitute the earliest steps in EMT and cancer invasion program; we wiil utilize the live chick chorioallantoic membrane to study these interactions and the role of Twist1 in HNSCC invasion in vivo. The study proposed in this application represents a collaborative effort between three departments at the University of Michigan and has the potential of defining molecular targets for improving treatment outcomes for patients with HNSCC. Funding for the proposed study would allow the principal investigator to interact with leaders in the field of EMT and HNSCC and to apply her knowledge of biochemistry and molecular biology to translational research.