Single-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis

Xuan-Zhang Huang, Min-Jiao Pang, Jia-Yi Li, Han-Yu Chen, Jing-Xu Sun, Yong-Xi Song, Hong-Jie Ni, Shi-Yu Ye, Shi Bai, Teng-Hui Li, Xin-Yu Wang, Jing-Yuan Lu, Jin-Jia Yang, Xun Sun, Jason C. Mills (), Zhi-Feng Miao () and Zhen-Ning Wang ()
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Xuan-Zhang Huang: The First Hospital of China Medical University
Min-Jiao Pang: The First Hospital of China Medical University
Jia-Yi Li: The First Hospital of China Medical University
Han-Yu Chen: The First Hospital of China Medical University
Jing-Xu Sun: The First Hospital of China Medical University
Yong-Xi Song: The First Hospital of China Medical University
Hong-Jie Ni: The First Hospital of China Medical University
Shi-Yu Ye: The First Hospital of China Medical University
Shi Bai: The First Hospital of China Medical University
Teng-Hui Li: The First Hospital of China Medical University
Xin-Yu Wang: The First Hospital of China Medical University
Jing-Yuan Lu: China Medical University, Shenyang, Liaoning province
Jin-Jia Yang: China Medical University, Shenyang, Liaoning province
Xun Sun: China Medical University
Jason C. Mills: Baylor College of Medicine
Zhi-Feng Miao: The First Hospital of China Medical University
Zhen-Ning Wang: The First Hospital of China Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36310-9

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