Forschung & Innovation
Publikationen
Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation
PMU Autor*in
Alexander W Eckert
Alle Autor*innen
Jonas Weiße, Julia Rosemann, Lisa Müller, Matthias Kappler, Alexander W Eckert, Markus Glaß, Danny Misiak, Stefan Hüttelmaier, Wolfgang G Ballhausen, Mechthild Hatzfeld, Monika Haemmerle, Tony Gutschner
Fachzeitschrift
MOLECULAR CANCER
Kurzfassung
BACKGROUND: Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy.
METHODS: We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis.
RESULTS: We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation.
CONCLUSION: Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.
Keywords
Humans, Carcinoma, Squamous Cell/genetics, Mouth Neoplasms/genetics, Antineoplastic Agents/pharmacology, Cell Line, Tumor, Cell Movement/drug effects, Dasatinib/pharmacology, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics, Neoplasm Invasiveness/genetics, Transcriptome