Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation.
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.
Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK.
Tyler F
TF
Hayes
Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK.
Nathan
N
Benaich
Department of Medicine, Central Clinical School, Level 6, Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004, Australia.
Stephen J
SJ
Goldie
Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK.
Kalle
K
Sipilä
Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK.
Ashley
A
Ames-Draycott
BGI-Shenzhen, Shenzhen 518038, China.
Wenjun
W
Cai
BGI-Shenzhen, Shenzhen 518038, China.
Guangliang
G
Yin
Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK. Electronic address: Fiona.watt@kcl.ac.uk.
Fiona M
FM
Watt
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection
D000970:Antineoplastic Agents; D015820:Cadherins; C502403:FAT1 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8; D019311:Staurosporine
Caspase 8; FAT1; Oral squamous cell carcinoma; Whole exome sequencing
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