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Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities
- Source :
- Neoplasia: An International Journal for Oncology Research, Vol 22, Iss 12, Pp 778-788 (2020), Neoplasia (New York, N.Y.)
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
Abstract
- Highlights • Laser-capture microdissection (LCM) followed by RNAseq reveals detailed insights into COSCC and molecular homologies to HNSCC. • Identification of CDK4/6 as therapeutic vulnerability in COSCC. • This 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.<br />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.
- Subjects :
- 0301 basic medicine
Cancer Research
Cellular differentiation
Cell
medicine.disease_cause
0302 clinical medicine
FFPE tissue
1306 Cancer Research
Dog Diseases
Original Research
Cell Cycle
RNA sequencing
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunohistochemistry
medicine.anatomical_structure
030220 oncology & carcinogenesis
Mouth Neoplasms
KRAS
Reprogramming
Epithelial-Mesenchymal Transition
palbociclib
10184 Institute of Veterinary Pathology
Laser Capture Microdissection
Biology
Palbociclib
lcsh:RC254-282
03 medical and health sciences
Dogs
medicine
Biomarkers, Tumor
Animals
Humans
CDK4/CDK6
E2F
neoplasms
Comparative oncology
Squamous Cell Carcinoma of Head and Neck
Gene Expression Profiling
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Oncogenes
10079 Institute of Veterinary Pharmacology and Toxicology
Laser-capture microdissection
Immune checkpoint
stomatognathic diseases
030104 developmental biology
Cancer cell
Cancer research
570 Life sciences
biology
Neoplasm Grading
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 14765586
- Volume :
- 22
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Neoplasia: An International Journal for Oncology Research
- Accession number :
- edsair.doi.dedup.....cfc066fe99ee554af46afc8dbc2acdb3