Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities.
Animals
Biomarkers, Tumor
Cell Cycle
/ genetics
Cyclin-Dependent Kinase 4
/ antagonists & inhibitors
Cyclin-Dependent Kinase 6
/ antagonists & inhibitors
Dog Diseases
/ etiology
Dogs
Epithelial-Mesenchymal Transition
/ genetics
Gene Expression Profiling
Humans
Immunohistochemistry
Laser Capture Microdissection
Mouth Neoplasms
/ etiology
Neoplasm Grading
Oncogenes
Squamous Cell Carcinoma of Head and Neck
/ etiology
Transcriptome
CDK4/CDK6
Comparative oncology
FFPE tissue
Laser-capture microdissection
RNA sequencing
palbociclib
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
13
07
2020
revised:
02
10
2020
accepted:
04
10
2020
pubmed:
4
11
2020
medline:
17
8
2021
entrez:
3
11
2020
Statut:
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.
Identifiants
pubmed: 33142242
pii: S1476-5586(20)30158-5
doi: 10.1016/j.neo.2020.10.003
pmc: PMC7642746
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
778-788Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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