Written by Charlotte Harrison, Science Writer
The tumour heterogeneity of gastric cancer, and its metastasis to different organs, makes effective treatment of this disease extremely difficult. We urgently need a better understanding of gastric tumour heterogeneity, and better mapping of organ-specific metastatic features.
To help achieve this aim, a study published in Clinical and Translational Medicine generated transcriptomics profiles of single cells from primary gastric tumours and different metastases sites using single-cell RNA sequencing (scRNA-seq). This powerful technique can provide information about the genetic profile of an individual cell in the context of its microenvironment.
Patient samples – one cell at a time
The study used ten tissue samples from six patients recently diagnosed with gastric cancer. The samples were from the primary tumour and adjacent non-tumour sites, as well as from six metastases from different tissues. These samples were evaluated using scRNA-seq. Validation experiments were conducted using histological assays and transcriptomic datasets (not single-cell) from the Cancer Genome Atlas database.
In total almost 43,000 cells were analysed using scRNA-seq. Unsupervised cell clustering was used to identify potential cell types, which detected seven distinct lineages — epithelial, stromal, proliferative, T cells, B cells, natural killer cells and myeloid cells — based on the expression of marker genes. The proportion of each cell lineage in primary tumours and metastases was highly variable, indicating that cells within gastric tumours and metastases are very heterogeneous.
Clues to gastric cancer progression and treatments
Further analysis showed that epithelial cells could be divided into four clusters, each with different phenotypes and functions. For example, clusters associated with invasion features, a propensity to undergo intraperitoneal metastasis, and a strong epithelial–mesenchymal transition phenotype, were discovered. Linking these clusters with previously published datasets showed these clusters were associated with poorer overall survival.
The authors also identified a signature based on the expression of 20 genes (found on dysfunctional T cells in the lymph nodes) that could predict metastasis of gastric cancer to the lymph nodes.
Moreover, an analysis to determine cell-to-cell interactions identified an interaction, HLA-E–KLRC1/KLRC2, that was predicted to occur between many cell types in the tumour micro-environment. Importantly, this result suggests that drugs that target KLRC1 (also called NKG2A; a receptor for natural killer cells), such as the monoclonal antibody monalizumab, could be a new therapeutic opportunity in gastric cancer.
This is one of the first studies to provide single-cell insight into the intra-tumour and inter-tumour heterogeneity of primary gastric tumours and organ metastases. Although the results need to be confirmed with larger sample sizes, these findings offer a route to personalised medicine for gastric cancer.
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