Genomic landscape and clonal architecture of mouse oral squamous cell carcinomas dictate tumour ecology

Inês Sequeira,Mamunur Rashid,Inês M Tomás,Marc J Williams,Trevor A Graham,David J Adams,Alessandra Vigilante,Fiona M Watt

doi:10.1038/s41467-020-19401-9

Abstract

To establish whether 4-nitroquinoline N-oxide-induced carcinogenesis mirrors the heterogeneity of human oral squamous cell carcinoma (OSCC), we have performed genomic analysis of mouse tongue lesions. The mutational signatures of human and mouse OSCC overlap extensively. Mutational burden is higher in moderate dysplasias and invasive SCCs than in hyperplasias and mild dysplasias, although mutations in p53, Notch1 and Fat1 occur in early lesions. Laminin-α3 mutations are associated with tumour invasiveness and Notch1 mutant tumours have an increased immune infiltrate. Computational modelling of clonal dynamics indicates that high genetic heterogeneity may be a feature of those mild dysplasias that are likely to progress to more aggressive tumours. These studies provide a foundation for exploring OSCC evolution, heterogeneity and progression.

Highlights

To establish whether 4-nitroquinoline N-oxide-induced carcinogenesis mirrors the heterogeneity of human oral squamous cell carcinoma (OSCC), we have performed genomic analysis of mouse tongue lesions
To overcome the limitations of current approaches to studying head and neck cancer, we have focused on an autologous mouse model of OSCC that most commonly affects the tongue
Lesions were identified and characterised macroscopically, and formalin-fixed and paraffin-embedded (FFPE) sections were analysed by microscopy (Fig. 1d, Supplementary Fig. 1a, Supplementary Data 1 and 2)

Summary

Introduction

To establish whether 4-nitroquinoline N-oxide-induced carcinogenesis mirrors the heterogeneity of human oral squamous cell carcinoma (OSCC), we have performed genomic analysis of mouse tongue lesions. Computational modelling of clonal dynamics indicates that high genetic heterogeneity may be a feature of those mild dysplasias that are likely to progress to more aggressive tumours These studies provide a foundation for exploring OSCC evolution, heterogeneity and progression. These effects are similar to the genetic alterations induced by tobacco carcinogens[19,21]. We conclude that the 4NQO carcinogenesis model captures many of the hallmarks of human OSCC

Methods

Results

Conclusion