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

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.