Publication Date
2-14-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-36310-9
PMID
36788228
PMCID
PMC9929081
PubMedCentral® Posted Date
2-14-2023
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Humans, Ascites, Peritoneal Neoplasms, Peritoneum, Stomach Neoplasms, Gastric cancer, Cancer microenvironment, Cancer microenvironment
Abstract
Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.
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