Data from Single-cell eQTL Mapping Reveals Cell Subtype–specific Genetic Control and Mechanism in Malignant Transformation of Colorectal Cancer

作者：Can Chen, Yimin Cai, Wenlong Hu, Kai Tan, Zequn Lu, Xuanyu Zhu, Ziying Liu, Chunyi He, Guangping Xu, Ruizhe Zhang, Caibo Ning, Shuheng Ruan, Jiayan Gao, Xiaojun Yang, Yongchang Wei, Xu Zhu, Xiangpan Li, Faxi Wang, Fubing Wang, Jiaoyuan Li, Meng Jin, Bin Li, Ying Zhu, Jianbo Tian, Xiaoping Miao · 年份：2025 · DOI：10.1158/2159-8290.c.7963854 · 被引用次数：1 · 研究领域：Single-cell and spatial transcriptomics、Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers

<div>AbstractColorectal cancer is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. In this study, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular cross-talk during colorectal cancer development. Additionally, we created a colorectal cancer single-cell expression quantitative trait locus (sc-eQTL) map identifying 16,833 significant pairs across 28 cell subtypes, with more than 76% of sc-eQTLs being cell type–specific and fewer than 15% detectable in bulk datasets. A polygenic risk score derived from sc-eQTLs substantially improved colorectal cancer risk prediction. We prioritized rs4794979 that is associated with an increased colorectal cancer risk (OR = 1.11, P = 2.04 × 10−12) by promoting LGALS9 expression mediated by ELK1. Elevated LGALS9 in epithelia interacts with SLC1A5 on fibroblasts, promoting transformation into cancer-associated fibroblasts and simultaneously inducing CD8+ T-cell exhaustion via the LGALS9–TIM3 axis, thereby facilitating colorectal cancer development. Blocking the LGALS9–TIM3 axis enhanced anti–PD-1 therapy to inhibit colorectal cancer progression.Significance:Our study provides a valuable resource, i...