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Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing
- Source :
- The Journal of pathologyReferences. 254(3)
- Publication Year :
- 2021
-
Abstract
- Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome caused by germline variants in CDH1, the gene encoding the cell-cell adhesion molecule E-cadherin. Loss of E-cadherin in cancer is associated with cellular dedifferentiation and poor prognosis, but the mechanisms through which CDH1 loss initiates HDGC are not known. Using single-cell RNA sequencing, we explored the transcriptional landscape of a murine organoid model of HDGC to characterize the impact of CDH1 loss in early tumourigenesis. Progenitor populations of stratified squamous and simple columnar epithelium, characteristic of the mouse stomach, showed lineage-specific transcriptional programs. Cdh1 inactivation resulted in shifts along the squamous differentiation trajectory associated with aberrant expression of genes central to gastrointestinal epithelial differentiation. Cytokeratin 7 (CK7), encoded by the differentiation-dependent gene Krt7, was a specific marker for early neoplastic lesions in CDH1 carriers. Our findings suggest that deregulation of developmental transcriptional programs may precede malignancy in HDGC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Subjects :
- 0301 basic medicine
Squamous Differentiation
Mice, Transgenic
Germline
Pathology and Forensic Medicine
CDH1
Cancer syndrome
03 medical and health sciences
Cytokeratin
Mice
0302 clinical medicine
Stomach Neoplasms
medicine
Animals
Genetic Predisposition to Disease
biology
Cancer
medicine.disease
Cadherins
3. Good health
Gene Expression Regulation, Neoplastic
Organoids
Disease Models, Animal
030104 developmental biology
Cell Transformation, Neoplastic
Single cell sequencing
030220 oncology & carcinogenesis
Cancer research
biology.protein
Hereditary diffuse gastric cancer
Single-Cell Analysis
Transcriptome
Subjects
Details
- ISSN :
- 10969896
- Volume :
- 254
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of pathologyReferences
- Accession number :
- edsair.doi.dedup.....b65dd2542ac96b0274d86b6d3e769545