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Single-Cell Sequencing for Precise Cancer Research: Progress and Prospects Xiaoyan Zhang1, Sadie L

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Single-Cell Sequencing for Precise Cancer Research: Progress and Prospects Xiaoyan Zhang1, Sadie L Published OnlineFirst March 3, 2016; DOI: 10.1158/0008-5472.CAN-15-1907 Cancer Review Research Single-Cell Sequencing for Precise Cancer Research: Progress and Prospects Xiaoyan Zhang1, Sadie L. Marjani2, Zhaoyang Hu1, Sherman M. Weissman3, Xinghua Pan1,3,4, and Shixiu Wu1 Abstract Advances in genomic technology have enabled the faithful could potentially improve the early detection and monitoring detection and measurement of mutations and the gene expres- of rare cancer cells, such as circulating tumor cells and dissem- sion profile of cancer cells at the single-cell level. Recently, inated tumor cells, and promote the development of person- several single-cell sequencing methods have been developed alized and highly precise cancer therapy. Here, we discuss that permit the comprehensive and precise analysis of the the current methods for single cancer-cell sequencing, with a cancer-cell genome, transcriptome, and epigenome. The use of strong focus on those practically used or potentially valuable these methods to analyze cancer cells has led to a series of in cancer research, including single-cell isolation, whole unanticipated discoveries, such as the high heterogeneity and genome and transcriptome amplification, epigenome profiling, stochastic changes in cancer-cell populations, the new driver multi-dimensional sequencing, and next-generation sequenc- mutations and the complicated clonal evolution mechanisms, ing and analysis. We also examine the current applications, and the novel identification of biomarkers of variant tumors. challenges, and prospects of single cancer-cell sequencing. These methods and the knowledge gained from their utilization Cancer Res; 76(6); 1–8. Ó2016 AACR. Introduction disease progression (4). However, the molecular profiling data, especially heterogeneity analysis, of these important cancer-cell Cancer is a significant cause of mortality worldwide. Cur- populations are limited. When dominant clones are killed in rently, clinical therapies do not produce complete resolution cancer therapy, other minor clones may replace them and lead to for most cancer patients due to insufficient understanding of cancer recurrence (5). Dynamic changes in cancer niches, which the molecular mechanisms for carcinogenesis and tumor pro- comprise various cell types, can affect the development, progres- gression (1). Single-cell sequencing (SCS) includes a set of sion, and metastasis of cancer (2), but the identification, charac- powerful and comprehensive techniques that can provide terization, and isolation of the distinct cancer niche components insight into these unknowns. is very difficult. Thus, a high-resolution strategy to effectively Important types of cancer cells include primary tumor cells, screen and systematically analyze the heterogeneity of these metastatic tumor cells, cancer stem cells (CSC), circulating tumor different cancer cells and cancer niche cells is desired and expected cells (CTC), and disseminated tumor cells (DTC; Fig. 1A). Primary to lead to a wave of unanticipated discoveries. tumor cells can often be described as variants of subpopulations Because mutagenesis, gene regulation, and genetic modifica- (1). Metastatic tumor cells usually include the original tumor cell tion occur intrinsically at the single-cell level, SCS will enable clones and differentially invasive and secondarily mutated cell highly precise, molecular characterization of carcinogenesis and clones. CSCs, which are often very rare, can undergo self-renewal, will hopefully resolve the important problems described above. are therapy resistant, and may cause the recurrence of cancer, This will lead to the identification of new biomarkers and drug can also be characterized into different cell subpopulations (2). targets and, in turn promote cancer diagnosis, monitoring, and CTCs and DTCs play a vital role in cancer dissemination, self- therapy (6). In this review, we summarize SCS methods recently renewal, and distant metastases (3). Cancer cells dispersed in an developed, including those that could be extremely useful, but individual or even forming a single tumor or a clone are often have not been applied in sequencing of single cancer cells. The heterogeneous, and this heterogeneity changes dynamically with clinical applications as well as the current problems and limita- tions of these technologies for use in the study of cancer are also 1Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, discussed. Zhejiang Province, P. R. China. 2Department of Biology, Central Con- necticut State University, New Britain, Connecticut. 3Department of Isolation of Single Cancer Cells Genetics,Yale University School of Medicine, New Haven, Connecticut. 4Department of Biochemistry, School of Basic Medical Sciences, South- Analysis of a single cancer cell initially requires the isolation of ern Medical University, Guangzhou, Guangdong Province, P.R. China. the desired type of cells based on classic phenotypes or surface Corresponding Authors: Xinghua Pan, Yale University, 300 Cedar Street, TAC- markers, in a way that preserves the biologic integrity of the cell. S320 New Haven, CT 06520. Phone: 203-589-1087; Fax: 203-737-2286; E-mail: When isolating single cells from solid tumors, dispersion of the [email protected], and Shixiu Wu, [email protected] tumor tissue into a single-cell suspension is necessary. Mechanical doi: 10.1158/0008-5472.CAN-15-1907 separation and enzymatic treatments are often used (7, 8; Fig. Ó2016 American Association for Cancer Research. 1B1). Isolation of CTCs from bodily fluids involves two types of www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 3, 2016; DOI: 10.1158/0008-5472.CAN-15-1907 Zhang et al. A Primary tumor Cancer cell Cancer niches Hematological tumor Solid tumor Metastatic tumor Peripheral blood types Tumor Tumor Epithelial cell Progenitor cells Cancer cells Disseminated Red blood cell Endothelial cell Cancer-associated fibroblast Biopsy materials tumor cells White blood cell Extracellular matrix Immune inflammatory cells Cancer stem cells Blood platelet Circulating tumor cell B1 Collagenases “Cloudy” interface layer “Cloudy” interface layer from bone marrow from peripheral blood Isolation of Tumor Tumor pieces single cancer cells (B1-1) (B1-2) (B1-3) FACS Microfluidics systems B2 Multispectral (i) Cancer circulating cell sorting (ii) Single cell trapping, lysis, RT and seq detectors Four Anti-EpCAM Cell Lysis buffer isolation Illumina methods trapping Laser RT seq Nano-magnetic Cell lysis reagents particle Discarded cells Magnet CTC RT Micromanipulation system Laser capture microdissection (11) (i) Micromanipulators (i) Cell selecting (ii) Laser cutting (iii) Cells on a transfer membrane (ii) Manual isolation CC C RT C=CpG Codetection: Future: GG scWGS scWES scGT-seq scRNA-seq scMT-seq scM-seq Single cell scATAC(60) sequencing (i) MDA (6, 14) (i) Physical (i) Full-length (i) Bisulfite-based MIDAS (15) separation-based Smart-Seq (30, 31) scRRBS (56, 57) Nuc-seq (16) Han’s method (64) PTA/STA (32) scBS (58) (ii) MALBAC (6, 18) G&T-seq (65) (ii) UMI-based … scWGBS (59) (iii) PCR (6, 17) (ii) Non-physical Islam’s UMI-WTA (34) (ii) Non-bisulfite-based separation-based (iii) in situ Seq … DR-seq (66) FISSEQ (35) Padlock-RCA (36) smFISH (37, 38) TIVA (39) (scWGS) (iv) Multiplexed STRT-seq (40, 41) Exome capture CEL-seq (42) (scWES) Quartz-seq (43) Fiuidigm C1 (12, 44) DropSeq (45, 46) Library construction and/or Sequencing / and Bioinformatic analysis © 2016 AAmerican i AAssociation i i ffor CCancer RResearch OF2 Cancer Res; 76(6) March 15, 2016 Cancer Research Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 3, 2016; DOI: 10.1158/0008-5472.CAN-15-1907 Single-Cell Sequencing of Cancer methods (Fig. 1B2). The first is biomarker dependent, such as the The MDA method is most popularly applied in WGA due to its CellSearch magnetic bead system. The second uses density-gra- high fidelity and simplicity. Several updated MDA kits are suitable dient centrifugation, microfiltration, or microfluidics systems. for single-cell WGA (scWGA), such as REPLI-g Single Cell Kit, The CTC capture platform CTC-IchIP, which relies on the inherent GenomiPhi DNA Amplification Kit, and AmpliQ Genomic differences in morphology or size between leukocytes and CTCs Amplifier Kit (14). Recently, a MDA system, called the micro- (9), can be used to isolate some CTCs without known biomarkers. well displacement amplification system (MIDAS), enabled the For DTC isolation, needle aspiration is used to collect bone simultaneous amplification of thousands of single cells marrow followed by single-cell sorting (10). through the use of hundreds to thousands of nanoliter wells, Single-cell sorting methods, including marker/phenotype- and the result was more robust with improved uniformity (15). based methods for isolating single cells from bulk cell popula- Amodified MDA approach, Nuc-seq, took advantage of the fact tions [FACS, microfluidics, micromanipulation, and laser cap- that a single cell in the G2–M stage of the cell cycle has four ture microdissection (LCM); Fig. 1B2] and from rare cell popu- copies of the genome and significantly increased the genome lations (CellSearch, DEP-Array, CellCelector, MagSweeper, and coverage (16). For PCR-based scWGA methods, the formulated nanofilters), have been well summarized previously (10, 11). kits
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