Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation

• Published in: Cancer letters Vol. 383; no. 1; pp. 106 - 114
• Main Authors: Hayes, Tyler F, Benaich, Nathan, Goldie, Stephen J, Sipilä, Kalle, Ames-Draycott, Ashley, Cai, Wenjun, Yin, Guangliang, Watt, Fiona M
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01-12-2016; Elsevier Limited; Elsevier Science Ireland
• Subjects: Alcohol; Antineoplastic Agents - pharmacology; Apoptosis; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Caspase 8; Caspase 8 - genetics; Caspase 8 - metabolism; Cell Adhesion; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Conflicts of interest; Databases, Genetic; Drug Resistance, Neoplasm; FAT1; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Genomics; Genomics - methods; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Hematology, Oncology and Palliative Medicine; Human papillomavirus; Humans; Mens health; Mortality; Mouth Neoplasms - drug therapy; Mouth Neoplasms - enzymology; Mouth Neoplasms - genetics; Mouth Neoplasms - pathology; Mutation; Neoplasm Invasiveness; Oral cancer; Oral squamous cell carcinoma; Original; Phenotype; RNA Interference; Signal Transduction; Software; Squamous Cell Carcinoma of Head and Neck; Staurosporine - pharmacology; Transfection; Tumors; Whole exome sequencing; FAT1; Caspase 8; Oral squamous cell carcinoma; whole exome sequencing; Whole exome sequencing
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2016.09.014

Abstract Oral squamous cell carcinoma (OSCC) is genetically highly heterogeneous, which contributes to the challenges of treatment. To create an in vitro model that accurately reflects this heterogeneity, we generated a panel of HPV-negative OSCC cell lines. By whole exome sequencing of the lines and matched patient blood samples, we demonstrate that the mutational spectrum of the lines is representative of primary OSCC in The Cancer Genome Atlas. We show that loss of function mutations in FAT1 (an atypical cadherin) and CASP8 (Caspase 8) frequently occur in the same tumour. OSCC cells with inactivating FAT1 mutations exhibited reduced intercellular adhesion. Knockdown of FAT1 and CASP8 individually or in combination in OSCC cells led to increased cell migration and clonal growth, resistance to Staurosporine-induced apoptosis and, in some cases, increased terminal differentiation. The OSCC lines thus represent a valuable resource for elucidating the impact of different mutations on tumour behaviour.