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Single-cell RNA sequencing reveals the tumor microenvironment and facilitates strategic choices to circumvent treatment failure in a chemorefractory bladder cancer patient

 Hye Won Lee  ;  Woosung Chung  ;  Hae-Ock Lee  ;  Da Eun Jeong  ;  Areum Jo  ;  Joung Eun Lim  ;  Jeong Hee Hong  ;  Do-Hyun Nam  ;  Byong Chang Jeong  ;  Se Hoon Park  ;  Kyeung-Min Joo  ;  Woong-Yang Park 
 GENOME MEDICINE, Vol.12(1) : 47, 2020-05 
Journal Title
Issue Date
Animals ; Antibodies, Monoclonal, Humanized / therapeutic use* ; Antineoplastic Agents / therapeutic use* ; Drug Resistance, Neoplasm / genetics* ; Humans ; Male ; Mice ; Middle Aged ; Proto-Oncogene Proteins p21(ras) / genetics ; Quinolones / therapeutic use* ; RNA-Seq ; Single-Cell Analysis ; Transcriptome / drug effects ; Treatment Failure ; Tumor Microenvironment / drug effects ; Tumor Microenvironment / genetics* ; Urinary Bladder Neoplasms / drug therapy* ; Urinary Bladder Neoplasms / genetics* ; Urinary Bladder Neoplasms / pathology
Treatment resistance ; Tumoral heterogeneity ; Tumor microenvironment ; Single-cell RNA sequencing ; Muscle-invasive urothelial bladder cancer
Background Tumor cell-intrinsic mechanisms and complex interactions with the tumor microenvironment contribute to therapeutic failure via tumor evolution. It may be possible to overcome treatment resistance by developing a personalized approach against relapsing cancers based on a comprehensive analysis of cell type-specific transcriptomic changes over the clinical course of the disease using single-cell RNA sequencing (scRNA-seq). Methods Here, we used scRNA-seq to depict the tumor landscape of a single case of chemo-resistant metastatic, muscle-invasive urothelial bladder cancer (MIUBC) addicted to an activating Harvey rat sarcoma viral oncogene homolog (HRAS) mutation. In order to analyze tumor evolution and microenvironmental changes upon treatment, we also applied scRNA-seq to the corresponding patient-derived xenograft (PDX) before and after treatment with tipifarnib, a HRAS-targeting agent under clinical evaluation. Results In the parallel analysis of the human MIUBC and the PDX, diverse stromal and immune cell populations recapitulated the cellular composition in the human and mouse tumor microenvironment. Treatment with tipifarnib showed dramatic anticancer effects but was unable to achieve a complete response. Importantly, the comparative scRNA-seq analysis between pre- and post-tipifarnib-treated PDX revealed the nature of tipifarnib-refractory tumor cells and the tumor-supporting microenvironment. Based on the upregulation of programmed death-ligand 1 (PD-L1) in surviving tumor cells, and the accumulation of multiple immune-suppressive subsets from post-tipifarnib-treated PDX, a PD-L1 inhibitor, atezolizumab, was clinically applied; this resulted in a favorable response from the patient with acquired resistance to tipifarnib. Conclusion We presented a single case report demonstrating the power of scRNA-seq for visualizing the tumor microenvironment and identifying molecular and cellular therapeutic targets in a treatment-refractory cancer patient.
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1. College of Medicine (의과대학) > Dept. of Hospital Medicine (입원의학과) > 1. Journal Papers
Yonsei Authors
Lee, Hye Won(이혜원)
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