Single-cell eQTL mapping reveals cell subtype-specific genetic control and mechanism in malignant transformation of colorectal cancer

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-03-03 DOI:10.1158/2159-8290.cd-24-1561

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

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引用次数: 0

Abstract

Colorectal cancer (CRC) is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. Here, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular crosstalk during CRC development. Additionally, we created a CRC sc-eQTL map identifying 16,833 significant pairs across 28 cell subtypes, with over 76% of sc-eQTLs being cell-type-specific and fewer than 15% detectable in bulk datasets. A polygenic risk score (PRS) derived from sc-eQTLs substantially improved CRC risk prediction. We prioritized rs4794979 that is associated with an increased CRC 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 (CAFs), simultaneously induces CD8+ T cells exhaustion via LGALS9-TIM3 axis, thereby facilitating CRC development. Blocking LGALS9-TIM3 axis enhanced anti-PD-1 therapy to inhibit CRC progression.

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单细胞eQTL定位揭示结直肠癌恶性转化的细胞亚型特异性遗传调控及机制

结直肠癌（CRC）是一种异质性疾病，通过逐步积累发展，但单细胞分辨率的潜在机制尚不清楚。在这里，我们分析了来自142个多阶段样本的751,531个单细胞转录组、空间转录组和snMultiomes，揭示了CRC发展过程中的细胞和分子改变以及动态的细胞间串扰。此外，我们创建了CRC sc-eQTL图谱，鉴定了28种细胞亚型中的16,833对重要染色体对，其中超过76%的sc-eQTL是细胞类型特异性的，在大量数据集中可检测到的不到15%。来自sc- eqtl的多基因风险评分（PRS）大大提高了CRC风险预测。我们优先考虑了通过促进ELK1介导的LGALS9表达而与CRC风险增加相关的rs4794979 （OR=1.11， P=2.04×10-12）。上皮中LGALS9的升高与成纤维细胞上的SLC1A5相互作用，促进成纤维细胞向癌症相关成纤维细胞（CAFs）的转化，同时通过LGALS9- tim3轴诱导CD8+ T细胞衰竭，从而促进结直肠癌的发展。阻断LGALS9-TIM3轴增强抗pd -1治疗抑制结直肠癌进展。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.