Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities

Franco Guscetti,Sina Nassiri,Erin Beebe,Inês Rito Brandao,Ramona Graf,Enni Markkanen

doi:10.1016/j.neo.2020.10.003

Abstract

Spontaneously occurring canine oral squamous cell carcinomas (COSCC) are viewed as a useful model for human head and neck squamous cell carcinomas (HNSCC). To date however, the molecular basis of COSCC remains poorly understood. To identify changes pertinent to cancer cells in COSCC, we specifically analyzed tumor cells and matched normal epithelium from clinical formalin-fixed paraffin-embedded specimens using laser-capture-microdissection coupled with RNA-sequencing (RNAseq). Our results identify strong contributions of epithelial-to-mesenchymal transition (EMT), classical tumor-promoting (such as E2F, KRAS, MYC, mTORC1, and TGFB1 signaling) and immune-related pathways in the tumor epithelium of COSCC. Comparative analyses of COSCC with 43 paired tumor/normal HNSCC from The Cancer Genome Atlas revealed a high homology in transcriptional reprogramming, and identified processes associated with cell cycle progression, immune processes, and loss of cellular differentiation as likely central drivers of the disease. Similar to HNSCC, our analyses suggested a ZEB2-driven partial EMT in COSCC and identified selective upregulation of KRT14 and KRT17 in COSCC. Beyond homology in transcriptional signatures, we also found therapeutic vulnerabilities strongly conserved between the species: these included increased expression of PD-L1 and CTLA-4, coinciding with EMT and revealing the potential for immune checkpoint therapies, and overexpression of CDK4/6 that sensitized COSCC to treatment with palbociclib. In summary, our data significantly extend the current knowledge of molecular aberrations in COSCC and underline the potential of spontaneous COSCC as a model for HNSCC to interrogate therapeutic vulnerabilities and support translation of novel therapies from bench to bedside.

Highlights

Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of epithelial tumors frequent in humans [1,2,3]
All of these genes showed significant expression changes consistent with RNAseq (Figure 1C–I). These findings demonstrate the validity of isolating tumor cells and matched normal epithelium from formalin-fixed paraffin-embedded (FFPE) tissue sections and their analysis by RNAseq and reveal the occurrence of vast transcriptional reprogramming in canine oral squamous cell carcinomas (COSCC)
We present a thorough transcriptome analysis of tumor cells and matched normal epithelium isolated from 10 cases of COSCC using laser-capture microdissection (LCM) of FFPE tissue coupled with RNAseq

Summary

Introduction

Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of epithelial tumors frequent in humans [1,2,3]. Based on the closely related pathophysiology, spontaneously occurring cancers in the domestic dog are increasingly viewed as valuable models to promote understanding of cancer biology and identify novel potential therapeutic targets [7,8,9]. Similar tumor types at similar locations between dogs and humans offer the possibility to overcome many of the limitations of xenograft or genetically modified rodent tumor models. This might apply for spontaneous canine oral squamous cell carcinomas (COSCC) that have been proposed as models for human HNSCC [10]. Given the metabolic similarities that allow extrapolation of toxicity-related preclinical data from dogs to humans, spontaneous tumors in dogs could serve as models to accelerate translation of novel therapeutic approaches from bench to bedside

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Results

Conclusion