GPRC5A promotes lung colonization of esophageal squamous cell carcinoma

Hongyu Zhou, Licheng Tan, Baifeng Zhang, Dora Lai Wan Kwong, Ching Ngar Wong, Yu Zhang, Beibei Ru, Yingchen Lyu, Kin To Hugo Siu, Jie Luo, Yuma Yang, Qin Liu, Yixin Chen, Weiguang Zhang, Chaohui He, Peng Jiang, Yanru Qin, Beilei Liu () and Xin-Yuan Guan ()
Additional contact information
Hongyu Zhou: The University of Hong Kong
Licheng Tan: The University of Hong Kong
Baifeng Zhang: The University of Hong Kong
Dora Lai Wan Kwong: The University of Hong Kong
Ching Ngar Wong: The University of Hong Kong
Yu Zhang: Sun Yat-Sen University Cancer Center
Beibei Ru: National Institutes of Health
Yingchen Lyu: The University of Hong Kong
Kin To Hugo Siu: The University of Hong Kong
Jie Luo: The University of Hong Kong
Yuma Yang: The University of Hong Kong
Qin Liu: The University of Hong Kong
Yixin Chen: Fudan University Shanghai Cancer Center
Weiguang Zhang: Fujian Medical University Union Hospital
Chaohui He: Songshan Lake Central Hospital of Dongguan City
Peng Jiang: National Institutes of Health
Yanru Qin: Zhengzhou University
Beilei Liu: The University of Hong Kong
Xin-Yuan Guan: The University of Hong Kong

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Emerging evidence suggests that cancer cells may disseminate early, prior to the formation of traditional macro-metastases. However, the mechanisms underlying the seeding and transition of early disseminated cancer cells (DCCs) into metastatic tumors remain poorly understood. Through single-cell RNA sequencing, we show that early lung DCCs from esophageal squamous cell carcinoma (ESCC) exhibit a trophoblast-like ‘tumor implantation’ phenotype, which enhances their dissemination and supports metastatic growth. Notably, ESCC cells overexpressing GPRC5A demonstrate improved implantation and persistence, resulting in macro-metastases in the lungs. Clinically, elevated GPRC5A level is associated with poorer outcomes in a cohort of 148 ESCC patients. Mechanistically, GPRC5A is found to potentially interact with WWP1, facilitating the polyubiquitination and degradation of LATS1, thereby activating YAP1 signaling pathways essential for metastasis. Importantly, targeting YAP1 axis with CA3 or TED-347 significantly diminishes early implantation and macro-metastases. Thus, the GPRC5A/WWP1/LATS1/YAP1 pathway represents a crucial target for therapeutic intervention in ESCC lung metastases.

Date: 2024
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DOI: 10.1038/s41467-024-54251-9

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