LMU, ENT Clinics and Helmholtz Center Munich, Molecular Oncology
ENT Clinics of LMU
Helmholtz Center Munich
Institute of Clinical Molecular Biology and Tumour Genetics
Department of Gene Vectors
+49 (89) 4400-73895
Fax: +49 (89) 4400-76896
Mapping effectors of local invasion in head and neck carcinomas
Over 600,000 new instances of head and neck squamous cell carcinoma (HNSCC) are diagnosed each year worldwide and the figure for these increases. Despite significant investments in developing HNSCC therapies, the 5-year survival rate of advanced HNSCC patients remains below 35%. A significant factor in metastasis formation in HNSCC is the epithelial-mesenchymal transition (EMT; the transformation of tumor cells from an epithelial to a mesenchymal phenotype).
In the Gires Lab, it has been demonstrated that epidermal growth factor receptor (EGFR)-mediated EMT, which is primarily transduced through mitogen-activated protein kinase (MAPK) activation and promotes migration and invasion, aids in the advancement of HNSCC. This finding was of particular interest as EGFR serves as target for the therapeutic monoclonal antibody Cetuximab in the adjuvant treatment of advanced HNSCC patients. An EGFR-mediated EMT gene signature was identified in cellular models (n=181 genes) that allowed the identification of a five-gene signature with prognostic value in HNSCC patients. DDIT4, FADD, ITGB4, NCEH1, and TIMP1 together make up that 5-gene risk score predicting overall survival (OS) in HNSCC patient cohorts.
Based on the findings on EMT in HNSCC, the aims of the project are two-fold. Firstly, we aim to further explore the novel regulatory networks of EGFR in HNSCC and identify gene signature(s) characterizing EGFR-mediated EMT from preclinical to clinical status to improve HNSCC stratification with a special focus on local recurrences, lymph node status, and response to EGFR-specific therapeutic agents. Secondly, we aim to identify prospective therapeutic targets, i.e. genes that make up EGFR-mediated signatures will be further described at the functional, molecular level in adequate cellular models.
1. scRNA-sequencing analysis of invasive and non-invasive cells in EGF/EGFR-induced EMT in HNSCCs cell lines and in primary budding tumor cells
2. Validation of the EMT gene signatures in clinical cohorts of HNSCC.
3. Assessment of the predictive value of the gene EMT-signature with respect to lymph node status, local recurrence, and response to EGFR-based treatments.
4. Study of the regulatory networks through NetBid2 (TFs and downstream targets) of EGF/EGFR-induced EMT in HNSCCs and inference of protein activity through (meta)Viper algorithms.
5. Exploration of the molecular function role and potential benefit of newly identified target genes to determine their role in EMT, metastases formation, and test their druggability in HNSCC pre-clinical models.
Must-have lab skills
• Cell culture of eukaryotic cell lines
• Molecular biology techniques (qRT-PCR, Immunoblotting, FACS)
• Interest in bioinformatic analysis of RNA sequencing datasets