Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity

Jihyun Kim,Soo Young Cho,Ki Taek Nam,Jong Kyu Woo,Eun Hye Kim,Charny Park,Je Kyung Seong,Hyunki Kim,Yong Chan Lee,Kwang H. Kim

doi:10.1038/s41698-022-00251-1

Abstract

Single-cell transcriptomic profiles analysis has proposed new insights for understanding the behavior of human gastric cancer (GC). GC offers a unique model of intratumoral heterogeneity. However, the specific classes of cells involved in carcinogenetic passage, and the tumor microenvironment of stromal cells was poorly understood. We characterized the heterogeneous cell population of precancerous lesions and gastric cancer at the single-cell resolution by RNA sequencing. We identified 10 gastric cell subtypes and showed the intestinal and diffuse-type cancer were characterized by different cell population. We found that the intestinal and diffuse-type cancer cells have the differential metaplastic cell lineages: intestinal-type cancer cells differentiated along the intestinal metaplasia lineage while diffuse-type cancer cells resemble de novo pathway. We observed an enriched CCND1 mutation in premalignant disease state and discovered cancer-associated fibroblast cells harboring pro-stemness properties. In particular, tumor cells could be categorized into previously proposed molecular subtypes and harbored specific subtype of malignant cell with high expression level of epithelial-myofibroblast transition which was correlated with poor clinical prognosis. In addition to intratumoral heterogeneity, the analysis revealed different cellular lineages were responsible for potential carcinogenetic pathways. Single-cell transcriptomes analysis of gastric pre-cancerous lesions and cancer may provide insights for understanding GC cell behavior, suggesting potential targets for the diagnosis and treatment of GC.

Highlights

Gastric cancer (GC) is the fourth most commonly occurring human cancer and the second most common cause of cancerrelated deaths worldwide, despite the global decrease in its incidence[1]
Recent studies incorporated in The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) revealed the usefulness of next-generation sequencing for the molecular classification of gastric cancer (GC), and identified its prognostic significance in independent cohorts[5,6]
Genetic evidence of the presence of stem cell (SC) population. Those genes we propose that the IGC cell lineage shows a neoplastic sets targeted by four embryonic stem (ES) cell regulators were activated both in progression pattern from intestinal metaplasia (IM) to tumor, and that IM might be a human ES cells and tumors[24]

Summary

INTRODUCTION

Gastric cancer (GC) is the fourth most commonly occurring human cancer and the second most common cause of cancerrelated deaths worldwide, despite the global decrease in its incidence[1]. The intra-genomic heterogeneity in GC provides the diversity of GC cell lineages in GC patients and 12gene signature appears to be fundamental to GC carcinogenesis as it is highly prognostic in GC cohort but performed just as robustly in several large scale localized GC cohorts[14]. All of these high-throughput methods used to analyze tumor plasticity have the limitations reproducing histopathology stages for the Correa’s hypothesis, extending prior to GC molecular subtypes in single cell resolution, and investigating inter-/intraheterogeneity for IGC and DGC. We classified the masked tumor cell signatures by single cell RNA sequencing (scRNA-seq) and bulk sequencing to identify the molecular markers of cell transition from the premalignant to malignant states in gastric carcinogenesis (Fig. 1a)

RESULTS

DISCUSSION

METHODS

Findings

CODE AVAILABILITY