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

Détails

ID Serval
serval:BIB_6ADE166E2DDA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities.
Périodique
Neoplasia
Auteur⸱e⸱s
Guscetti F., Nassiri S., Beebe E., Rito Brandao I., Graf R., Markkanen E.
ISSN
1476-5586 (Electronic)
ISSN-L
1476-5586
Statut éditorial
Publié
Date de publication
12/2020
Peer-reviewed
Oui
Volume
22
Numéro
12
Pages
778-788
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
Animals, Biomarkers, Tumor, Cell Cycle/genetics, Cyclin-Dependent Kinase 4/antagonists & inhibitors, Cyclin-Dependent Kinase 6/antagonists & inhibitors, Dog Diseases/etiology, Dog Diseases/metabolism, Dog Diseases/pathology, Dog Diseases/therapy, Dogs, Epithelial-Mesenchymal Transition/genetics, Gene Expression Profiling, Humans, Immunohistochemistry, Laser Capture Microdissection, Mouth Neoplasms/etiology, Mouth Neoplasms/metabolism, Mouth Neoplasms/pathology, Mouth Neoplasms/therapy, Neoplasm Grading, Oncogenes, Squamous Cell Carcinoma of Head and Neck/etiology, Squamous Cell Carcinoma of Head and Neck/metabolism, Squamous Cell Carcinoma of Head and Neck/pathology, Squamous Cell Carcinoma of Head and Neck/therapy, Transcriptome, CDK4/CDK6, Comparative oncology, FFPE tissue, Laser-capture microdissection, RNA sequencing, palbociclib
Pubmed
Web of science
Open Access
Oui
Création de la notice
09/11/2020 9:39
Dernière modification de la notice
16/04/2024 7:11
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