2. Academic Validation
  3. GPRC5A promotes lung colonization of esophageal squamous cell carcinoma

GPRC5A promotes lung colonization of esophageal squamous cell carcinoma

  • Nat Commun. 2024 Nov 16;15(1):9950. doi: 10.1038/s41467-024-54251-9.
Hongyu Zhou # 1,  Licheng Tan # 1,  Baifeng Zhang # 1 2 3,  Dora Lai Wan Kwong 1,  Ching Ngar Wong 1,  Yu Zhang 4 5,  Beibei Ru 6,  Yingchen Lyu 1,  Kin To Hugo Siu 1,  Jie Luo 1 2 3,  Yuma Yang 1 2 3,  Qin Liu 1,  Yixin Chen 7,  Weiguang Zhang 8,  Chaohui He 9,  Peng Jiang 6,  Yanru Qin 10,  Beilei Liu 11 12 13,  Xin-Yuan Guan 14 15 16 17 18
Affiliations

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. bella007@connect.hku.hk.
  • 12 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. bella007@connect.hku.hk.
  • 13 Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. bella007@connect.hku.hk.
  • 14 Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. xyguan@hku.hk.
  • 15 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. xyguan@hku.hk.
  • 16 Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. xyguan@hku.hk.
  • 17 Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China. xyguan@hku.hk.
  • 18 MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China. xyguan@hku.hk.
  • # 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.

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