GPRC5A promotes lung colonization of esophageal squamous cell carcinoma

Abstract

Recent studies suggest that cancer cells can begin to spread in the early stages, even prior to the emergence of conventional macro-metastases. However, the processes that enable these early disseminated cancer cells (DCCs) to establish and grow into metastatic tumors are still not well understood. Esophageal carcinoma, particularly esophageal squamous cell carcinoma (ESCC), plays a major role in the occurrence of metastatic cancers and ranks as the seventh leading cause of cancer-related deaths among men worldwide, with a poor prognosis for individuals with distant metastases. Lung metastasis, along with metastases to lymph nodes and the liver, presents significant challenges in managing ESCC patients. In the present study, we employ single-cell RNA sequencing (scRNA-seq) to demonstrate that early lung DCCs from ESCC display a trophoblastic cell-like “tumor implantation (TI)” phenotype, facilitating their early spread and supplying vital factors for metastatic development. By employing scRNA-seq, multiplex immunofluorescence, and an in-vivo mouse model of pulmonary metastasis, we identify the upregulation of the GPRC5A gene, known for its role in trophoblast-mediated embryo implantation, as a key driver of the TI-like program in cancer cells. Notably, our findings reveal that ESCC cells expressing GPRC5A have an increased ability to effectively implant, survive, and persist, ultimately leading to the formation of metastatic nodules in the mouse lungs. Clinically, high GPRC5A expression correlates with advanced tumor stages, lymph node metastases, lymphovascular invasion, and distant metastases in 148 ESCC patients from our in-house cohort. Mechanistically, our findings suggest that GPRC5A might collaborate with WWP1 to facilitate LATS1 poly-ubiquitination, resulting in its ubiquitin-dependent degradation, which in turn relieves LATS1-mediated degradation of YAP1 in the cytoplasm. This process promotes YAP1's translocation to the nucleus, activating downstream signaling pathways that facilitate tumor implantation and metastasis. Importantly, targeting YAP1 therapeutically can significantly inhibit the tumor implantation-like program and subsequent macro-metastases in the lungs in vivo. In conclusion, we propose that the GPRC5A mediated-WWP1/LATS1/YAP1 axis is essential for driving lung micro-metastases and macro-metastases of ESCC. Inhibiting this axis with CA3 or TED-347 may reduce metastatic potential and provide therapeutic benefits for ESCC patients.