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

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.

Dissecting the Single-Cell Transcriptome Network in Superficial/Deep Tumor Tissues of Diffuse Gastric Cancer

“…As the most promising biotechnology de ned by Nature Methods in 2013, single-cell sequencing shows superior advantages in the identi cation of inter-tumoral heterogeneity and intra-tumoral heterogeneity recent years [15,16]. Actually, single-cell sequencing has already been applied to investigate the heterogeneity in gastric cancer and speci c genes have been identi ed to be responsible for the malignance of gastric cancer, such as OR51E1 [17], Gkn3 [18], and Krt7 [19].…”

Applications and Achievements of Single-Cell Sequencing in Gastrointestinal Cancer

“…SCS helps to clarify the molecular level mechanism of the immune cells in the tumor microenvironment during tumor cell generation, development, metastasis, drug resistance and immune escape. It contributes to a more accurate clinical diagnosis, treatment, and prognosis of solid tumors ( 19 , 20 ). In the past few years, several researchers have made significant advances in microenvironmental research by using SCS to analyze GC cells ( Table 2 ).…”

“…Analysis of the SCS data from mice with hereditary diffuse gastric cancer (HDGC) revealed that inactivation of Cdh1 led to metastasis along the squamous cell differentiation trajectory associated with aberrant expression of GI epithelial differentiation center genes. Cytokeratin 7 encoded by the differentiation-dependent gene Krt7, was a specific marker of early neoplastic lesions in CDH1 carriers ( 20 ). In conclusion, SCS is valuable in identifying prognostic tumor markers for predicting potential clinical outcomes and immune responses, as well as, for individualized therapy.…”

The Single-Cell Sequencing: A Dazzling Light Shining on the Dark Corner of Cancer

“…Moreover, TME-specific helper T cells, cytotoxic T cells, Tregs, and NK cells were found to express multiple immune checkpoint and costimulatory molecules ( 58 ). In addition, CDH1 loss resulted in shifts along the squamous differentiation trajectory, as well as the aberrant expression of the KRT7 gene (encoding the CK7 protein), which was identified as the top candidate leading to gastrointestinal epithelial invasion and early metastasis in CDH1 carriers ( 59 ). Chromatin accessibility has been identified as one of the most relevant genomic characteristics associated with oncologic functions at a specific site, providing the structure for transcription TFs binding to regulate multiple genes, thus driving cancer progression and invasion ( 60 ).…”