Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing.

Autor: Dixon K; Department of Medical Genetics, University of British Columbia, Vancouver, Canada., Brew T; Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand., Farnell D; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada., Godwin TD; Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand., Cheung S; Division of Anatomic Pathology, Vancouver Coastal Health, Vancouver, Canada., Chow C; Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, Canada., Ta M; Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, Canada., Ho G; Department of Molecular Oncology, BC Cancer, Vancouver, Canada., Bui M; Department of Molecular Oncology, BC Cancer, Vancouver, Canada., Douglas JM; Department of Molecular Oncology, BC Cancer, Vancouver, Canada., Campbell KR; Department of Molecular Oncology, BC Cancer, Vancouver, Canada., El-Naggar A; Department of Molecular Oncology, BC Cancer, Vancouver, Canada.; Department of Pathology, Menoufia University, Shibin El Kom, Egypt., Kaurah P; Hereditary Cancer Program, BC Cancer, Vancouver, Canada., Kalloger SE; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada., Lim HJ; Department of Medical Oncology, BC Cancer, Vancouver, Canada., Schaeffer DF; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.; Division of Anatomic Pathology, Vancouver Coastal Health, Vancouver, Canada., Cochrane D; Department of Molecular Oncology, BC Cancer, Vancouver, Canada., Guilford P; Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand., Huntsman DG; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Jazyk: angličtina
Zdroj: The Journal of pathology [J Pathol] 2021 Jul; Vol. 254 (3), pp. 254-264. Date of Electronic Publication: 2021 May 12.
DOI: 10.1002/path.5675
Abstrakt: 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.
(© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
Databáze: MEDLINE
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