Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
Nat Commun. 2024 Nov 16;15(1):9950. doi: 10.1038/s41467-024-54251-9.
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.
新出现的证据表明，癌细胞可能在形成传统的宏观转移之前就早期扩散。然而，早期播散的癌细胞（DCC）向转移性肿瘤播种和转变的机制仍知之甚少。通过单细胞 RNA 测序，我们表明食管鳞癌（ESCC）的早期肺 DCC 表现出滋养层样“肿瘤植入”表型，这增强了它们的扩散并支持转移性生长。值得注意的是，过表达 GPRC5A 的 ESCC 细胞表现出改善的植入和持久性，导致肺部发生大转移。临床上，在 148 名 ESCC 患者的队列中，升高的 GPRC5A 水平与更差的预后相关。在机制上，发现 GPRC5A 可能与 WWP1 相互作用，促进 LATS1 的多泛素化和降解，从而激活对转移至关重要的 YAP1 信号通路。重要的是，用 CA3 或 TED-347 靶向 YAP1 轴可显著减少早期植入和大转移。因此，GPRC5A/WWP1/LATS1/YAP1 通路是 ESCC 肺转移治疗干预的一个关键靶点。
