Deconvolution of cell type-specific drug responses in human tumor tissue with single-cell RNA-seq

Genome Medicine

Michael B. Sisti¹  Jeffrey N. Bruce¹  Eleonora Francesca Spinazzi¹  Pavan Upadhyayula¹  Marc L. Otten¹  Matei Alexandru Banu¹  Tejaswi Sudhakar¹  Peter Canoll²  Athanassios Dovas²  Tamara Marie²  Hanna Mendes Levitin³  Wenting Zhao³  Peter A. Sims⁴ 

[1] Department of Neurological Surgery, Columbia University Irving Medical Center, 10032, New York, NY, USA;Department of Pathology & Cell Biology, Columbia University Irving Medical Center, 10032, New York, NY, USA;Department of Systems Biology, Columbia University Irving Medical Center, 10032, New York, NY, USA;Department of Systems Biology, Columbia University Irving Medical Center, 10032, New York, NY, USA;Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, 10032, New York, NY, USA;Department of Biochemistry & Molecular Biophysics, Columbia University Irving Medical Center, 10032, New York, NY, USA;

关键词: Glioblastoma;    Single-cell RNA sequencing (scRNA-seq);    Tissue slice culture;    Tumor heterogeneity;    Drug perturbation;    Etoposide;    Panobinostat;    Tumor microenvironment;   

DOI  :  10.1186/s13073-021-00894-y

来源: Springer

【 摘 要 】

BackgroundPreclinical studies require models that recapitulate the cellular diversity of human tumors and provide insight into the drug sensitivities of specific cellular populations. 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.MethodsWe 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 drug perturbations on slices derived from six glioblastoma (GBM) resections to identify conserved drug responses and to one additional GBM resection to identify patient-specific responses.ResultsWe used scRNA-seq to demonstrate that acute slice cultures recapitulate the cellular and molecular features of the originating tumor tissue and the feasibility of drug screening from an individual tumor. 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. Etoposide has a conserved impact on proliferating tumor cells, while panobinostat treatment affects both tumor and non-tumor populations, including unexpected effects on the immune microenvironment.ConclusionsAcute slice cultures recapitulate the major cellular and molecular features of GBM at the single-cell level. In combination with scRNA-seq, this approach enables cell type-specific analysis of sensitivity to multiple drugs in individual tumors. We anticipate that this approach will facilitate pre-clinical studies that identify effective therapies for solid tumors.

【 授权许可】

CC BY