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; Xin-Yuan Guan

doi:10.1038/s41467-024-54251-9

GPRC5A promotes lung colonization of esophageal squamous cell carcinoma

Nat Commun. 2024 Nov 16;15(1):9950. doi: 10.1038/s41467-024-54251-9.

Authors

Hongyu Zhou^#¹, Licheng Tan^#¹, Baifeng Zhang^#^{1

2

3}, Dora Lai Wan Kwong¹, Ching Ngar Wong¹, Yu Zhang^{4

5}, Beibei Ru⁶, Yingchen Lyu¹, Kin To Hugo Siu¹, Jie Luo^{1

2

3}, Yuma Yang^{1

2

3}, Qin Liu¹, Yixin Chen⁷, Weiguang Zhang⁸, Chaohui He⁹, Peng Jiang⁶, Yanru Qin¹⁰, Beilei Liu^{11

12

13}, Xin-Yuan Guan^{14

15

16

17

18}

Affiliations

¹ Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
² Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
³ Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
⁴ Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
⁵ State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
⁶ Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Liver Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁸ Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
⁹ Department of Cardiovascular Surgery, Songshan Lake Central Hospital of Dongguan City, Dongguan, China.
¹⁰ Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
¹¹ Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. [email protected].
¹² Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. [email protected].
¹³ Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. [email protected].
¹⁴ Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. [email protected].
¹⁵ Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. [email protected].
¹⁶ Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. [email protected].
¹⁷ Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China. [email protected].
¹⁸ MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China. [email protected].

^# Contributed equally.

PMID: 39550386
DOI: 10.1038/s41467-024-54251-9

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Cell Line, Tumor
Esophageal Neoplasms* / genetics
Esophageal Neoplasms* / metabolism
Esophageal Neoplasms* / pathology
Esophageal Squamous Cell Carcinoma* / genetics
Esophageal Squamous Cell Carcinoma* / metabolism
Esophageal Squamous Cell Carcinoma* / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Lung Neoplasms* / secondary
Male
Mice
Mice, Nude
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism
Receptors, G-Protein-Coupled* / genetics
Receptors, G-Protein-Coupled* / metabolism
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism
Ubiquitination
YAP-Signaling Proteins* / genetics
YAP-Signaling Proteins* / metabolism

Substances

Receptors, G-Protein-Coupled
GPRC5A protein, human
YAP-Signaling Proteins
YAP1 protein, human
LATS1 protein, human
Ubiquitin-Protein Ligases
Protein Serine-Threonine Kinases
Transcription Factors
Adaptor Proteins, Signal Transducing