Assessing clonal evolution in head and neck squamous cell carcinoma and its contribution to tumor progression and treatment resistance

• Applicants: Dr. Konrad Klinghammer; Privatdozent Dr. Kristoffer Riecken; Professorin Dr. Ingeborg Tinhofer-Keilholz
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467261817

Head and neck squamous cell carcinoma (HNSCC) is a deadly cancer that arises from the epithelium of the upper aero-digestive tract. The main cause of patient death is treatment failure leading to terminal progression of disease at local, regional and distant locations. This collaborative, Swiss-German (Lausanne, Berlin, Hamburg) research project is designed to study the clonal mechanisms underlying treatment failures in order to eventually identify new targets for therapeutic intervention.One of the hypotheses underlying the project is that treatment failure after radiation therapy is caused by a small subpopulation of tumor cells (so-called clones) harboring treatment resistance. Moreover, recurrences that recur at the original tumor site after complete surgical removal of the tumor bulko might be driven by a few remaining cancer cells that have evaded surgical removal by migrating into the surrounding tissue.The project is built on already existing cooperations between the three partners and will profit from the unique knowhow, model systems and technologies established in their laboratories. These tools include (i) extensively characterized, patient-derived HNSCC in-vivo models and three-dimensional (3D) cultures [Berlin]; (ii) advanced lentiviral vectors for cellular barcoding using novel barcode libraries compatible with single-cell RNA sequencing and designed for high-precision clonal tracking [Hamburg]; (iii) preclinical mouse models that allow studying clonal progression of HNSCC under standard-of-care therapy at unprecedented cellular and molecular resolution [Lausanne]; and (iv) many years of experience with the CRISPR-Cas9 gene scissors to elucidate the causal relationships between genetics and biology of tumor cells [Hamburg, Lausanne].We expect that a precise understanding of the biology of therapy-resistant tumor cell clones and their molecular characteristics will enable us to develop new treatment modalities for therapy-resistant tumors. This project can therefore make a significant contribution to optimizing therapy and improving the prognosis of patients with head and neck tumors.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Co-Investigator: Professor Dr. Boris Fehse
• Cooperation Partner: Privatdozent Genrich Tolstonog, Ph.D.