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Mutations in long-lived epithelial stem cells and their clonal progeny in pre-malignant lesions and in oral squamous cell carcinoma
- Source :
- Carcinogenesis
- Publication Year :
- 2020
- Publisher :
- Oxford University Press (OUP), 2020.
-
Abstract
- Oral squamous cell carcinomas (OSCCs) are the most common cancers of the oral cavity, but the molecular mechanisms driving OSCC carcinogenesis remain unclear. Our group previously established a murine OSCC model based on a 10-week carcinogen [4-nitroquinoline 1-oxide (4-NQO)] treatment. Here we used K14CreERTAM;Rosa26LacZ mice to perform lineage tracing to delineate the mutational profiles in clonal cell populations resulting from single, long-lived epithelial stem cells, here called LacZ+ stem cell clones (LSCCs). Using laser-capture microdissection, we examined mutational changes in LSCCs immediately after the 10-week 4-NQO treatment and >17 weeks after 4-NQO treatment. We found a 1.8-fold ±0.4 (P = 0.009) increase in single-nucleotide variants and insertions/deletions (indels) in tumor compared with pre-neoplastic LSCCs. The percentages of indels and of loss of heterozygosity events were 1.3-fold±0.3 (P = 0.02) and 2.2-fold±0.7 (P = 0.08) higher in pre-neoplastic compared with tumor LSCCs. Mutations in cell adhesion- and development-associated genes occurred in 83% of the tumor LSCCs. Frequently mutated genes in tumor LSCCs were involved in planar cell polarity (Celsr1, Fat4) or development (Notch1). Chromosomal amplifications in 50% of the tumor LSCCs occurred in epidermal growth factor receptor, phosphoinositide 3-kinase and cell adhesion pathways. All pre-neoplastic and tumor LSCCs were characterized by key smoking-associated changes also observed in human OSCC, C>A and G>T. DeconstructSigs analysis identified smoking and head and neck cancer as the most frequent mutational signatures in pre-neoplastic and tumor LSCCs. Thus, this model recapitulates a smoking-associated mutational profile also observed in humans and illustrates the role of LSCCs in early carcinogenesis and OSCCs.
- Subjects :
- 0301 basic medicine
Cancer Research
Carcinogenesis
Cell
Mice, Transgenic
medicine.disease_cause
Loss of heterozygosity
Mice
03 medical and health sciences
0302 clinical medicine
medicine
Animals
Cell Lineage
Epidermal growth factor receptor
Cell adhesion
Microdissection
Mutation
biology
Stem Cells
Epithelial Cells
General Medicine
4-Nitroquinoline-1-oxide
Clone Cells
Gene Expression Regulation, Neoplastic
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Carcinogens
Carcinoma, Squamous Cell
Cancer research
biology.protein
Mouth Neoplasms
Stem cell
Precancerous Conditions
Subjects
Details
- ISSN :
- 14602180 and 01433334
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Carcinogenesis
- Accession number :
- edsair.doi.dedup.....7472b7724e279719efe3786d0c25307e