PO.BCS01.09 · 生物信息与计算
基于单细胞的人类小细胞肺癌蛋白活性图谱
A single cell-based protein activity landscape for human small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
小细胞肺癌（SCLC）是一种致死性恶性肿瘤，其特征为快速转移、深刻的瘤内异质性（ITH）和免疫抑制性肿瘤免疫微环境（TIME）。SCLC的潜在生物学机制尚不清楚，治疗选择仍然有限。为克服这一问题，我们对一个大型基于单细胞RNA-Seq的SCLC人类样本队列进行了系统分析，以定义驱动SCLC ITH和TIME组成的基因调控网络和主调控因子（MR）。我们构建了一个单细胞转录组图谱，包含来自41例新鲜患者来源SCLC样本（原发部位和转移部位）的182,189个细胞。对肿瘤细胞和免疫细胞进行编目和聚类。为超越转录状态，我们使用ARACNe逆向工程构建了患者特异性和聚类特异性的调控网络，并通过metaVIPER推断了超过6,500个调控和信号蛋白的蛋白活性。该蛋白活性图谱被用于解构ITH和TIME构架。OncoTreat算法识别出可在匹配SCLC细胞系中逆转MR活性的FDA批准药物，随后进行了体内验证。我们的蛋白活性分析识别出由特定MR程序调控的、具有明确转化相关性的SCLC肿瘤和TIME亚群。在肿瘤细胞中，我们定义了一个增殖性的"肿瘤检查点"MR模块，作为这一侵袭性疾病的关键决定因素。在TIME中，我们发现了具有独特生物学特性的免疫亚群。一项全基因组药物扰动筛选识别出能有效消除肿瘤特异性MR活性的强效药物。这些候选药物在临床前体内模型中显示出诱导肿瘤细胞死亡的显著疗效。我们呈现了迄今为止最大的SCLC单细胞蛋白活性图谱，为其ITH和TIME背后的调控网络提供了高分辨率视图。我们通过计算推导并在临床前验证了靶向不同肿瘤和免疫亚群主调控因子的新型治疗策略，为克服SCLC的治疗耐药提供了一条有前景的途径。
查看英文原文 English abstract
Small cell lung cancer (SCLC) is a lethal malignancy characterized by rapid metastasis, profound intra-tumor heterogeneity (ITH), and an immunosuppressive tumor immune microenvironment (TIME). The underlying biology of SCLC is poorly understood, and treatment options remain limited. To overcome this, we performed a systematic analysis on a large collection of single-cell RNA-Seq-based SCLC human sample cohort to define the gene regulatory networks and master regulators (MR) driving SCLC ITH and TIME composition. We constructed a single-cell transcriptomic atlas of 182,189 cells from 41 fresh patient-derived SCLC samples (primary and metastatic sites). Tumor and immune cells were cataloged and clustered. To move beyond transcriptional states, we reverse-engineered patient- and cluster-specific regulatory networks using ARACNe and inferred protein activity for >6,500 regulatory and signaling proteins via metaVIPER. This protein activity landscape was used to deconvolute ITH and TIME architecture. The OncoTreat algorithm identified FDA-approved drugs that invert MR activity in matched SCLC cell lines, with subsequent in vivo validation. Our protein activity analysis identified distinct, translationally relevant SCLC tumor and TIME subpopulations governed by specific MR programs. In tumor cells, we defined a proliferative "Tumor Checkpoint" module of MRs as a key determinant of this aggressive disease. Within the TIME, we discovered immune subpopulations with unique biological properties. A genome-wide drug perturbation screen identified potent agents that effectively abrogate the activity of tumor-specific MRs. These candidates demonstrated significant efficacy in inducing tumor cell death in preclinical in vivo models. We present the largest single-cell protein activity atlas of SCLC, providing a high-resolution view of the regulatory networks underlying its ITH and TIME. We computationally derived and preclinically validated novel therapeutic strategies that target master regulators of distinct tumor and immune subpopulations, offering a promising path to overcome therapeutic resistance in SCLC.
利益披露 Disclosure
L. Hu, None.