-
Journal of Hematology & Oncology Jun 2021Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and... (Review)
Review
Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.
Topics: Animals; Epigenesis, Genetic; Gene Expression Profiling; Genomics; Humans; Neoplasms; Neoplastic Cells, Circulating; Sequence Analysis, DNA; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 34108022
DOI: 10.1186/s13045-021-01105-2 -
Signal Transduction and Targeted Therapy Nov 2021Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic... (Review)
Review
Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.
Topics: Biomarkers, Tumor; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Neoplastic Cells, Circulating; Prognosis
PubMed: 34803167
DOI: 10.1038/s41392-021-00817-8 -
Cell Reports Aug 2022Circulating tumor cells (CTCs) are the seeds of distant metastasis, and the number of CTCs detected in the blood of cancer patients is associated with a worse prognosis.... (Review)
Review
Circulating tumor cells (CTCs) are the seeds of distant metastasis, and the number of CTCs detected in the blood of cancer patients is associated with a worse prognosis. CTCs face critical challenges for their survival in circulation, such as anoikis, shearing forces, and immune surveillance. Thus, understanding the mechanisms and interactions of CTCs within the blood microenvironment is crucial for better understanding of metastatic progression and the development of novel treatment strategies. CTCs interact with different hematopoietic cells, such as platelets, red blood cells, neutrophils, macrophages, natural killer (NK) cells, lymphocytes, endothelial cells, and cancer-associated fibroblasts, which can affect CTC survival in blood. This interaction may take place either via direct cell-cell contact or through secreted molecules. Here, we review interactions of CTCs with blood cells and discuss the potential clinical relevance of these interactions as biomarkers or as targets for anti-metastatic therapies.
Topics: Biology; Biomarkers, Tumor; Blood Cells; Cell Count; Endothelial Cells; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Tumor Microenvironment
PubMed: 36044866
DOI: 10.1016/j.celrep.2022.111298 -
EBioMedicine Sep 2022Circulating tumor cells (CTCs) are tumor cells that shed from the primary tumor and intravasate into the peripheral blood circulation system responsible for metastasis.... (Review)
Review
Circulating tumor cells (CTCs) are tumor cells that shed from the primary tumor and intravasate into the peripheral blood circulation system responsible for metastasis. Sensitive detection of CTCs from clinical samples can serve as an effective tool in cancer diagnosis and prognosis through liquid biopsy. Current CTC detection technologies mainly reply on the biomarker-mediated platforms including magnetic beads, microfluidic chips or size-sensitive microfiltration which can compromise detection sensitivity due to tumor heterogeneity. A more sensitive, biomarker independent CTCs isolation technique has been recently developed with the surface-charged superparamagnetic nanoprobe capable of different EMT subpopulation CTC capture from 1 mL clinical blood. In this review, this new strategy is compared with the conventional techniques on biomarker specificity, impact of protein corona, effect of glycolysis on cell surface charge, and accurate CTC identification. Correlations between CTC enumeration and molecular profiling in clinical blood and cancer prognosis are provided for clinical cancer management.
Topics: Biomarkers, Tumor; Cell Separation; Humans; Liquid Biopsy; Neoplastic Cells, Circulating; Prognosis; Protein Corona
PubMed: 36041264
DOI: 10.1016/j.ebiom.2022.104237 -
Journal of Hepatology Dec 2021Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives...
BACKGROUND & AIMS
Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis.
METHODS
We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA.
RESULTS
Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer.
CONCLUSIONS
Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy.
LAY SUMMARY
Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.
Topics: Biopsy; Carcinoma, Hepatocellular; Cholangiocarcinoma; Humans; Immunotherapy; Liver Neoplasms; Neoplastic Cells, Circulating
PubMed: 34216724
DOI: 10.1016/j.jhep.2021.06.028 -
Nature Biotechnology Aug 2012Genome-wide transcriptome analyses are routinely used to monitor tissue-, disease- and cell type–specific gene expression, but it has been technically challenging to...
Genome-wide transcriptome analyses are routinely used to monitor tissue-, disease- and cell type–specific gene expression, but it has been technically challenging to generate expression profiles from single cells. Here we describe a robust mRNA-Seq protocol (Smart-Seq) that is applicable down to single cell levels. Compared with existing methods, Smart-Seq has improved read coverage across transcripts, which enhances detailed analyses of alternative transcript isoforms and identification of single-nucleotide polymorphisms. We determined the sensitivity and quantitative accuracy of Smart-Seq for single-cell transcriptomics by evaluating it on total RNA dilution series. We found that although gene expression estimates from single cells have increased noise, hundreds of differentially expressed genes could be identified using few cells per cell type. Applying Smart-Seq to circulating tumor cells from melanomas, we identified distinct gene expression patterns, including candidate biomarkers for melanoma circulating tumor cells. Our protocol will be useful for addressing fundamental biological problems requiring genome-wide transcriptome profiling in rare cells.
Topics: Animals; Cluster Analysis; Female; Gene Expression Profiling; Gene Library; Humans; Melanoma; Mice; Neoplastic Cells, Circulating; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Sensitivity and Specificity; Sequence Analysis, RNA
PubMed: 22820318
DOI: 10.1038/nbt.2282 -
Nature Cell Biology Dec 2018Tumours comprise a heterogeneous collection of cells with distinct genetic and phenotypic properties that can differentially promote progression, metastasis and drug... (Review)
Review
Tumours comprise a heterogeneous collection of cells with distinct genetic and phenotypic properties that can differentially promote progression, metastasis and drug resistance. Emerging single-cell technologies provide a new opportunity to profile individual cells within tumours and investigate what roles they play in these processes. This Review discusses key technological considerations for single-cell studies in cancer, new findings using single-cell technologies and critical open questions for future applications.
Topics: Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Single-Cell Analysis; Tumor Microenvironment
PubMed: 30482943
DOI: 10.1038/s41556-018-0236-7 -
Cell Feb 2017Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of... (Review)
Review
Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of research concerning metastasis continues to grow at a rapid rate, the biological programs that underlie the dissemination and metastatic outgrowth of cancer cells are beginning to come into view. In this review we summarize the cellular and molecular mechanisms involved in metastasis, with a focus on carcinomas where the most is known, and we highlight the general principles of metastasis that have begun to emerge.
Topics: Animals; Blood Platelets; Carcinoma; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Neutrophils; T-Lymphocytes; Tumor Microenvironment
PubMed: 28187288
DOI: 10.1016/j.cell.2016.11.037 -
Nature Jan 2016Metastasis is the main cause of death in people with cancer. To colonize distant organs, circulating tumour cells must overcome many obstacles through mechanisms that we... (Review)
Review
Metastasis is the main cause of death in people with cancer. To colonize distant organs, circulating tumour cells must overcome many obstacles through mechanisms that we are only now starting to understand. These include infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds and eventually breaking out to replace the host tissue. They make metastasis a highly inefficient process. However, once metastases have been established, current treatments frequently fail to provide durable responses. An improved understanding of the mechanistic determinants of such colonization is needed to better prevent and treat metastatic cancer.
Topics: Animals; Cell Proliferation; Cell Survival; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Organ Specificity; Stem Cell Niche; Tumor Microenvironment
PubMed: 26791720
DOI: 10.1038/nature17038 -
Molecular Cell Jul 2019Bulk genomic analyses and expression profiling of clinical specimens have shaped much of our understanding of cancer in patients. However, human tumors are intricate... (Review)
Review
Bulk genomic analyses and expression profiling of clinical specimens have shaped much of our understanding of cancer in patients. However, human tumors are intricate ecosystems composed of diverse cells, including malignant, immune, and stromal subsets, whose precise characterization is masked by bulk genomic methods. Single-cell genomic techniques have emerged as powerful approaches to dissect human tumors at the resolution of individual cells, providing a compelling approach to deciphering cancer biology. Here, we discuss some of the common themes emerging from initial studies of single-cell RNA sequencing in cancer and then highlight challenges in cancer biology for which emerging single-cell genomics methods may provide a compelling approach.
Topics: Antineoplastic Agents; Cell Communication; Cell Line, Tumor; Cell Lineage; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Neoplasms; Neoplastic Cells, Circulating; RNA, Neoplasm; Single-Cell Analysis
PubMed: 31299208
DOI: 10.1016/j.molcel.2019.05.003