Abstract P14: Lgr5+ and Lgr6+ Cells as Prognostic Markers and Therapeutic Targets in Esophageal Squamous Cell Carcinoma (ESCC)

Abstract

Esophageal squamous cell carcinoma (ESCC) is the world’s 7th most common malignancy, yet survival remains dismal owing to late detection, frequent relapse, and a lack of targeted therapies. While Wnt signalling is commonly dysregulated in ESCC, the specific roles of its facultative components Lgr5 and Lgr6 remain poorly understood. We combined single-cell transcriptomic analyses from patient biopsies, a chemically induced murine ESCC model, and primary three-dimensional tumour organoids to define how Lgr5+ and Lgr6+ epithelial cells shape disease course. Single-cell profiling of patient tumours located the majority of LGR5+ and LGR6+ cells within stem-like clusters enriched for cell-cycle and stress-adaptation programmes. In mice, reporter models showed that the proportion of Lgr5+ and Lgr6+ cells increases sharply between healthy tissues, dysplastic tissues, and tumours, while lineage tracing models confirmed their direct contribution to tumour outgrowth and long-term retention. In vitro organoid assays revealed functional complementarity: Lgr5+ cells enhanced organoid initiation, while Lgr6+ cells sustained long-term self-renewal. Collectively, these results label Lgr5+ and Lgr6+ populations as non-redundant drivers of tumour initiation and progression. Joint assessment of both markers sharpens prognostic resolution and exposes a dual-target vulnerability that could dismantle the cellular reservoir underpinning ESCC maintenance and relapse. This integrative study provides a rationale for precision interventions aimed at stem-like epithelial populations in ESCC and lays the groundwork for biomarker-guided therapeutic strategies.