Cell-of-Origin Analysis of Metastatic Gastric Cancer Uncovers the Origin of Inherent Intratumor Heterogeneity and a Fundamental Prognostic Signature

Abstract

Intra-tumoral heterogeneity (ITH) is the fundamental property of cancer, however, the origin of ITH remains poorly understood. Here we performed single-cell RNA sequencing of peritoneal carcinomatosis (PC) from 20 patients with advanced gastric adenocarcinoma (GAC), constructed a transcriptome map of 45,048 PC cells, determined the cell-of-origin of each tumor cell, and incisively explored ITH of PC tumor cells at single-cell resolution. The links between cell-of-origin and ITH was illustrated at transcriptomic, genotypic, molecular, and phenotypic levels. This study characterized the origins of PC tumor cells that populate and thrive in the peritoneal cavity, uncovered the diversity in tumor cell-of-origins and defined it as a key determinant of ITH. Furthermore, cell-of-origin-based analysis classified PC into two cellular subtypes that were prognostic independent of clinical variables, and a 12-gene prognostic signature was then derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis/progression and could be practical for patient stratification.

Proliferative and quiescent human gastric cancer stem-like cells are associated with differential chemoresistance and patient mortality

“…E1 cell dominant patients were largely diagnosed as diffuse, while E2 cell dominant patients' samples had the histological appearance of intestinal tissue. In the single-cell study on peritoneal metastasis of GC, Wang et al (2019) stratified patients into two groups: gastric type wherein the peritoneal carcinomatosis cells resembled stomach cells, and GI-mixed type wherein the tissue contained cells that resembled intestinal and other non-gastric cells types from the GI tract (Wang et al, 2019). Based on available clinical data, the gastric type patients had poorer prognosis than GI-mixed patients.…”

“…Meanwhile, the CXCR4 signaling pathway is frequently observed to be upregulated in highly invasive GC and tumor EMT (Xiang et al, 2017). Taken together, the activation of these pathways help to explain the poorer prognosis of the E1-dominant or diffuse GC patients compared to E2-dominant or intestinal GC patients (Petrelli et al, 2017;Wang et al, 2019).…”

“…Sathe et al reported intra-and inter-tumor transcription heterogeneity among tumor and infiltrated immune cells, as well as ligand-receptor interactions between different cell types (Sathe et al, 2020). Wang et al analyzed scRNA-seq of peritoneal carcinomatosis samples from GC patients and developed a panel of genes to stratify patients for survival (Wang et al, 2019). These studies employed the 10X Genomics Chromium system, which is highly popular due to its low cost per cell and the ability to assay large number of cells per run.…”