Publications
Detailed Information
Impact of intratumoral heterogeneity on drug responses: Unmasked by single-cell transcriptome analysis
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 묵인희 | - |
dc.contributor.author | 김규태 | - |
dc.date.accessioned | 2017-07-14T01:43:53Z | - |
dc.date.available | 2017-07-14T01:43:53Z | - |
dc.date.issued | 2015-08 | - |
dc.identifier.other | 000000067006 | - |
dc.identifier.uri | https://hdl.handle.net/10371/122291 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 의과학과 의과학전공, 2015. 8. 묵인희. | - |
dc.description.abstract | Introduction: Understanding distinct genomic signatures of a patients cancer is required to design and predict accurate therapeutic responses. Current approaches regarding heterogeneous cancer cells en masse as a pooled population, however, hardly reflect complete genomic landscape of tumor diversity, missing potentially important minor subclones implications such as metastasis and drug resistance.
Methods: To dissect intratumoral heterogeneity and discover unique patterns of subclonal behaviors against drug treatment responses in functional modalities and signaling pathways out of heterogeneous population derived from a cancer patient, tumor transcriptome was characterized at single-cell resolution by utilizing single-cell RNA sequencing (scRNA-seq). Results: First, in a lung adenocarcinoma PDX model*, individual cells showed mosaic expression of SNVs and differential gene expression. We could cluster the PDX cells into three distinct groups according to the presence of KRAS G12D mutation and transcriptome-based risk scores (RS). A single cell group with KRAS G12D/high RS was activated in the RAS-MAPK signaling pathway, and targeted by anti-cancer drugs such as docetaxel and BKM120. In comparison, a KRAS G12D/low RS group showed inactive RAS-MAPK signaling despite the expression of KRAS G12D. The drug-resistant population recapitulated gene expression signatures of the KRAS G12D/ low-RS group. Second, in a metastatic renal cell carcinoma PDX model, enriched subclonality was identified in a metastasis tumor with activated expression signatures of epithelial-mesenchymal transition and poor prognosis. Integrated analysis of transcriptome profiling and drug screening identified the most effective anti-cancer drugs. Furthermore, singularity of single cells with mutually exclusive activation of EGFR and SRC signaling pathways could suggest the potential of combination therapy, and its efficacy was validated in 2D and 3D in vitro and in vivo models. Conclusions: Patient-derived xenograft cells showed heterogeneous profiles in SNVs and gene expression, which could cluster them into subclones with differential responses to anti-cancer drugs. Taken together, our approach of single-cell RNA sequencing on tumors provides insights into the more accurate strategy to identify minor but potentially important subclones that are relevant to drug resistance. | - |
dc.description.tableofcontents | Introduction 14
1. Dissection of intratumoral heterogeneity (ITH) 15 2-1. Lung adenocarcinoma 15 2-2. Renal cell carcinoma 16 3. Patient-derived xenograft (PDX) model 17 4. Single-cell transcriptome analysis 18 Materials and Methods 20 Results 36 Part-I. Identification of tumor cell subgroups associated with anti-cancer drug resistance in a lung adenocarcinoma patient 36 I-1. Intratumoral genetic heterogeneity of LUAD PDX cells 37 I-2. Single-cell heterogeneity of expressed single-nucleotide variants (SNVs) 39 I-3. Identification of PDX cell subgroups 41 I-4. Phenotypic interpretation of PDX cell subgroups 42 I-5. Validation of analytical procedures in an independent lung cancer PDX case 44 Part-II. Translation of single cell expression signatures into therapeutics for a metastatic renal cell carcinoma patient 76 II-1. Enrichment of subclonal cancer cells in paired lung metastasis 77 II-2. Prediction of effective drug selection from single cell transcriptome profiles 79 Discussion 95 References 100 Abstract in Korean 107 | - |
dc.format | application/pdf | - |
dc.format.extent | 16593951 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Single cell analysis | - |
dc.subject | Lung adenocarcinoma | - |
dc.subject | Renal cell carcionma | - |
dc.subject | Patient-derived xenograft | - |
dc.subject | Tumor heterogeneity | - |
dc.subject | Drug response | - |
dc.subject.ddc | 610 | - |
dc.title | Impact of intratumoral heterogeneity on drug responses: Unmasked by single-cell transcriptome analysis | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.citation.pages | ix, 96 | - |
dc.contributor.affiliation | 의과대학 의과학과 | - |
dc.date.awarded | 2015-08 | - |
- Appears in Collections:
- Files in This Item:
Item View & Download Count
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.