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. 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

精准肿瘤学需要为个体患者及时遴选有效的药物或药物联合方案。理想的平台应可直接在患者肿瘤组织中快速筛选细胞类型特异性药物敏感性，并揭示克服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处理，与单细胞RNA测序（single-cell RNA sequencing，简称scRNA-seq）相结合，以解析个体患者全转录组水平的药物响应特征。我们将该方法应用于胶质母细胞瘤（GBM）研究，证实急性切片培养可重现来源肿瘤组织的细胞与分子特征。针对急性切片培养中的依托泊苷（etoposide，一种拓扑异构酶毒剂）及组蛋白去乙酰化酶（HDAC）抑制剂帕比司他（Panobinostat）开展的详细研究显示，多名患者中存在细胞类型特异性的药物响应，包括对免疫微环境的意外影响。我们预计该方法将助力快速、个性化的药物筛选，为实体瘤筛选出有效的治疗方案。本研究对人脑胶质瘤手术标本的活检组织，以及经不同药物处理的人脑胶质瘤手术标本急性切片培养物开展了scRNA-seq测序。