Deconvolution of Cell Type-Specific Drug Responses in Human Tumor Tissue with Single-Cell RNA-seq. Deconvolution of Cell Type-Specific Drug Responses in Human Tumor Tissue with Single-Cell RNA-seq

Precision oncology requires the timely selection of effective drugs or drug combinations for individual patients. The ideal platform would enable rapid screening of cell type-specific drug sensitivities directly in patient tumor tissue and reveal strategies to overcome intratumoral heterogeneity. Here we combine multiplexed drug perturbation in acute slice culture from freshly resected tumors with single-cell RNA sequencing (scRNA-seq) to profile transcriptome-wide drug responses in individual patients. We applied this approach to glioblastoma (GBM) and demonstrated that acute slice cultures recapitulate the cellular and molecular features of the originating tumor tissue. Detailed investigation of etoposide, a topoisomerase poison, and the histone deacetylase (HDAC) inhibitor Panobinostat in acute slice cultures revealed cell type-specific responses across multiple patients, including unexpected effects on the immune microenvironment. We anticipate that this approach will facilitate rapid, personalized drug screening to identify effective therapies for solid tumors. Overall design: Performed single-cell RNA-seq on biopsies of human glioma surgical specimens and on acute slice cultures of human glioma surgical specimens treated with various drugs

精准肿瘤学（Precision Oncology）需为个体患者及时筛选有效药物或联合用药方案。理想的技术平台应可直接在患者肿瘤组织中快速筛查细胞类型特异性药物敏感性，并揭示破解肿瘤内异质性的策略。本研究将新鲜切除肿瘤的急性切片培养中的多重药物扰动，与单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）相结合，以解析个体患者的全转录组药物应答特征。我们将该方法应用于胶质母细胞瘤（glioblastoma, GBM），证实急性切片培养可重现其来源肿瘤组织的细胞与分子特征。针对拓扑异构酶毒剂依托泊苷（etoposide）与组蛋白去乙酰化酶（HDAC）抑制剂帕比司他（Panobinostat）的急性切片培养研究，揭示了多例患者中不同细胞类型的特异性应答，包括对免疫微环境的意外调控效应。我们预计该方法将助力快速、个性化的药物筛选，为实体瘤患者确定有效治疗方案。实验设计概述：对人脑胶质瘤手术标本活检样本，以及经多种药物处理的人脑胶质瘤手术标本急性切片培养物，开展单细胞RNA测序。