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.
Highlights
The global annual incidence of head and neck squamous cell carcinoma (HNSCC) is approximately 600,000, with over 300,000 deaths attributable to the disease each year [1]
While many investigators have generated cell lines from human HNSCC and used them to study the biology of this tumour type [14e16], our study is the first to derive cell lines for which matching normal patient DNA is available
As proof of the utility of the lines, we studied the impact of loss of functional CASP8 and FAT1, two genetic changes that, we found, frequently occur together in individual Oral squamous cell carcinoma (OSCC)
Summary
The global annual incidence of head and neck squamous cell carcinoma (HNSCC) is approximately 600,000, with over 300,000 deaths attributable to the disease each year [1]. HNSCC lesions frequently recur and metastasize to other locations, contributing to significant morbidity and mortality [2]. Despite improvements in surgical care and adjuvant therapy, the 5-year survival rate is only 60% in the United States [3]. Previous studies have used next-generation whole exome sequencing of primary tumours to reveal the mutational landscapes of human HNSCCs and suggest novel oncogenic drivers to target for potential therapies [4e6]. HNSCC is strikingly heterogeneous at both the genetic and the cellular level. No single genetic lesion predominates and patients often develop more than one primary tumour
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