ena-STUDY-FUNCTIONAL GENOMICS CENTER ZURICH-03-09-2019-13:50:19:907-127
Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities
Spontaneously occurring canine oral squamous cell carcinoma (COSCC) are viewed as a useful model for human oropharyngeal 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 analysed tumour cells and matched normal epithelium from clinical FFPE (formalin-fixed paraffin-embedded) specimens using laser-capture-microdissection (LCM) coupled with next-generation-RNA-sequencing (RNAseq). Our results identify strong contributions of epithelial-to-mesenchymal transition (EMT), classical tumour-promoting (such as E2F, KRAS, MYC, mTORC1 and TGFB1 signalling) and immune-related pathways in the tumour epithelium of COSCC. Unbiased comparative analyses of COSCC with 43 paired tumour/normal HNSCC specimens revealed a high homology in transcriptional reprogramming, and identified processes associated with EMT, regulation of cell cycle progression through the CDK4/6-E2F axis, as well as mTORC1 and PDGF signalling 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 to be strongly conserved between the species: these included increased expression of PD-L1 and CTLA-4 coinciding with EMT, revealing the potential for immune checkpoint therapies, and overexpression of CDK4/6 that sensitised COSCC to treatment with palbociclib. In summary, our data significantly extends the current knowledge of molecular aberrations in COSCC, and underlines the potential of spontaneous COSCC as a model for HNSCC to interrogate therapeutic vulnerabilities and support translation of novel therapies from bench to bedside.
Spontaneously occurring canine oral squamous cell carcinoma (COSCC) are viewed as a useful model for human oropharyngeal 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 analysed tumour cells and matched normal epithelium from clinical FFPE (formalin-fixed paraffin-embedded) specimens using laser-capture-microdissection (LCM) coupled with next-generation-RNA-sequencing (RNAseq). Our results identify strong contributions of epithelial-to-mesenchymal transition (EMT), classical tumour-promoting (such as E2F, KRAS, MYC, mTORC1 and TGFB1 signalling) and immune-related pathways in the tumour epithelium of COSCC. Unbiased comparative analyses of COSCC with 43 paired tumour/normal HNSCC specimens revealed a high homology in transcriptional reprogramming, and identified processes associated with EMT, regulation of cell cycle progression through the CDK4/6-E2F axis, as well as mTORC1 and PDGF signalling 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 to be strongly conserved between the species: these included increased expression of PD-L1 and CTLA-4 coinciding with EMT, revealing the potential for immune checkpoint therapies, and overexpression of CDK4/6 that sensitised COSCC to treatment with palbociclib. In summary, our data significantly extends the current knowledge of molecular aberrations in COSCC, and underlines the potential of spontaneous COSCC as a model for HNSCC to interrogate therapeutic vulnerabilities and support translation of novel therapies from bench to bedside.