• Title, Summary, Keyword: cellular heterogeneity

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Dissecting Cellular Heterogeneity Using Single-Cell RNA Sequencing

  • Choi, Yoon Ha;Kim, Jong Kyoung
    • Molecules and Cells
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    • v.42 no.3
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    • pp.189-199
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    • 2019
  • Cell-to-cell variability in gene expression exists even in a homogeneous population of cells. Dissecting such cellular heterogeneity within a biological system is a prerequisite for understanding how a biological system is developed, homeostatically regulated, and responds to external perturbations. Single-cell RNA sequencing (scRNA-seq) allows the quantitative and unbiased characterization of cellular heterogeneity by providing genome-wide molecular profiles from tens of thousands of individual cells. A major question in analyzing scRNA-seq data is how to account for the observed cell-to-cell variability. In this review, we provide an overview of scRNA-seq protocols, computational approaches for dissecting cellular heterogeneity, and future directions of single-cell transcriptomic analysis.

Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs)

  • Nam, Sorim;Lee, Aram;Lim, Jihyun;Lim, Jong-Seok
    • Biomolecules & Therapeutics
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    • v.27 no.1
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    • pp.63-70
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    • 2019
  • Myeloid-derived suppressor cells (MDSCs) that are able to suppress T cell function are a heterogeneous cell population frequently observed in cancer, infection, and autoimmune disease. Immune checkpoint molecules, such as programmed death 1 (PD-1) expressed on T cells and its ligand (PD-L1) expressed on tumor cells or antigen-presenting cells, have received extensive attention in the past decade due to the dramatic effects of their inhibitors in patients with various types of cancer. In the present study, we investigated the expression of PD-1 on MDSCs in bone marrow, spleen, and tumor tissue derived from breast tumor-bearing mice. Our studies demonstrate that PD-1 expression is markedly increased in tumor-infiltrating MDSCs compared to expression in bone marrow and spleens and that it can be induced by LPS that is able to mediate $NF-{\kappa}B$ signaling. Moreover, expression of PD-L1 and CD80 on $PD-1^+$ MDSCs was higher than on $PD-1^-$ MDSCs and proliferation of MDSCs in a tumor microenvironment was more strongly induced in $PD-1^+$ MDSCs than in $PD-1^-$ MDSCs. Although we could not characterize the inducer of PD-1 expression derived from cancer cells, our findings indicate that the study on the mechanism of PD-1 induction in MDSCs is important and necessary for the control of MDSC activity; our results suggest that $PD-1^+$ MDSCs in a tumor microenvironment may induce tumor development and relapse through the modulation of their proliferation and suppressive molecules.

A New Perspective on the Heterogeneity of Cancer Glycolysis

  • Neugent, Michael L.;Goodwin, Justin;Sankaranarayanan, Ishwarya;Yetkin, Celal Emre;Hsieh, Meng-Hsiung;Kim, Jung-whan
    • Biomolecules & Therapeutics
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    • v.26 no.1
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    • pp.10-18
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    • 2018
  • Tumors are dynamic metabolic systems which highly augmented metabolic fluxes and nutrient needs to support cellular proliferation and physiological function. For many years, a central hallmark of tumor metabolism has emphasized a uniformly elevated aerobic glycolysis as a critical feature of tumorigenecity. This led to extensive efforts of targeting glycolysis in human cancers. However, clinical attempts to target glycolysis and glucose metabolism have proven to be challenging. Recent advancements revealing a high degree of metabolic heterogeneity and plasticity embedded among various human cancers may paint a new picture of metabolic targeting for cancer therapies with a renewed interest in glucose metabolism. In this review, we will discuss diverse oncogenic and molecular alterations that drive distinct and heterogeneous glucose metabolism in cancers. We will also discuss a new perspective on how aberrantly altered glycolysis in response to oncogenic signaling is further influenced and remodeled by dynamic metabolic interaction with surrounding tumor-associated stromal cells.

Single-Cell Sequencing in Cancer: Recent Applications to Immunogenomics and Multi-omics Tools

  • Sierant, Michael C.;Choi, Jungmin
    • Genomics & Informatics
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    • v.16 no.4
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    • pp.17.1-17.6
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    • 2018
  • Tumor heterogeneity, the cellular mosaic of multiple lineages arising from the process of clonal evolution, has continued to thwart multi-omics analyses using traditional bulk sequencing methods. The application of single-cell sequencing, in concert with existing genomics methods, has enabled high-resolution interrogation of the genome, transcriptome, epigenome, and proteome. Applied to cancers, these single-cell multi-omics methods bypass previous limitations on data resolution and have enabled a more nuanced understanding of the evolutionary dynamics of tumor progression, immune evasion, metastasis, and treatment resistance. This review details the growing number of novel single-cell multi-omics methods applied to tumors and further discusses recent discoveries emerging from these approaches, especially in regard to immunotherapy.

Software development for assessing cellular heterogeneity and its clinical application in gadoxetic acid-enhanced MRI of hepatocellular carcinoma (세포 이질성 평가 소프트웨어 개발과 가도세틱산 조영증강 자기공명영상을 이용한 간세포암종 환자에의 적용)

  • Kim, Tae-Hoon;Ryu, Jong-Hyun;Jeong, Chang-Won;Jun, Hong Young;Heo, Dong-Woon;Kang, Sung-Chan;Kim, Dae Won;Yoon, Kwon-Ha
    • Proceedings of the Korea Information Processing Society Conference
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    • pp.1446-1447
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    • 2015
  • In this paper, we developed the quantification software for evaluating the voxel-based cellular heterogeneity of gadoxetic acid-enhanced magnetic resonance imaging (MRI) in the liver. Our software is clinically applied to accurately quantify and interpret the alterations of liver functions in patients with hepatocellular carcinoma.

An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts

  • Cho, Sung-Yup;Kang, Wonyoung;Han, Jee Yun;Min, Seoyeon;Kang, Jinjoo;Lee, Ahra;Kwon, Jee Young;Lee, Charles;Park, Hansoo
    • Molecules and Cells
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    • v.39 no.2
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    • pp.77-86
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    • 2016
  • Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.

MicroRNAs as critical regulators of the endothelial to mesenchymal transition in vascular biology

  • Kim, Jongmin
    • BMB Reports
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    • v.51 no.2
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    • pp.65-72
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    • 2018
  • The endothelial to mesenchymal transition (EndMT) is a newly recognized, fundamental biological process involved in development and tissue regeneration, as well as pathological processes such as the complications of diabetes, fibrosis and pulmonary arterial hypertension. The EndMT process is tightly controlled by diverse signaling networks, similar to the epithelial to mesenchymal transition. Accumulating evidence suggests that microRNAs (miRNAs) are key regulators of this network, with the capacity to target multiple messenger RNAs involved in the EndMT process as well as in the regulation of disease progression. Thus, it is highly important to understand the molecular basis of miRNA control of EndMT. This review highlights the current fund of knowledge regarding the known links between miRNAs and the EndMT process, with a focus on the mechanism that regulates associated signaling pathways and discusses the potential for the EndMT as a therapeutic target to treat many diseases.

Asymptotic Approach to Analyze the Mechanical Properties of Biological Cells

  • Park, Soyeun
    • Journal of the Korean Physical Society
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    • v.70 no.10
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    • pp.918-923
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    • 2017
  • The Hertz model assuming a small indentation over the infinite hemisphere has been most widely applied to calculate elastic moduli of biological cells from data obtained by atomic force microscopy (AFM)-based indentation experiments. Previously reported experiments were mostly performed with a low stress to satisfy the Hertz assumption. In spite of its importance, mechanical heterogeneity observed in the high stress regime is often ignored due to the violation of the Hertz assumption. In this study, we have performed the hyperbolic fit modified from the Hertz model considering the asymptotic behaviors of layered structures in order to corroborate this issue. We demonstrate that our asymptotic approach confirmed the self-consistent elastic behavior of the cell cortex regardless of the applied stress regime. In addition, we have determined the elastic moduli of cellular regions beyond the cell cortex, where previous AFM indentation experiments could not easily access. We conclude that our asymptotic approach using hyperbolic fits provides a new empirically analytic mean to quantify the mechanical properties of biological cells including the high stress regime.

Cancer Stem Cells and Response to Therapy

  • Tabarestani, Sanaz;Ghafouri-Fard, Soudeh
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.12
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    • pp.5947-5954
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    • 2012
  • The cancer stem cell (CSC) model states that cancers are organized in cellular hierarchies, which explains the functional heterogeneity often seen in tumors. Like normal tissue stem cells, CSCs are capable of self-renewal, either by symmetric or asymmetric cell division, and have the exclusive ability to reproduce malignant tumors indefinitely. Current systemic cancer therapies frequently fail to eliminate advanced tumors, which may be due to their inability to effectively target CSC populations. It has been shown that embryonic pathways such as Wnt, Hedgehog, and Notch control self-renewal and cell fate decisions of stem cells and progenitor cells. These are evolutionary conserved pathways, involved in CSC maintenance. Targeting these pathways may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance.

Ganglioside as a Therapy Target in Various Types of Cancer

  • Qamsari, Elmira Safaie;Nourazarian, Alireza;Bagheri, Salman;Motallebnezhad, Morteza
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.4
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    • pp.1643-1647
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    • 2016
  • Since their discovery in 1940, it has been well established that gangliosides are associated with a number of biological pathways and cellular processes such as growth, differentiation and toxin uptake. Gangliosides are glycosphingolipids containing neuraminic acid which are expressed on the plasma membrane of cells particularly in the nervous system. Heterogeneity and structural variation in the carbohydrate chains of gangliosides contributes to unique features of each of these molecules. Thirty five years ago it was discovered that aberrant glycosylation occurs in a variety of human cancers, including aberrant glycosylation of gangliosides. Ganglioside expression in terms of quality and quantity varies in different cancers and different roles may be played. Gangliosides, by affecting the immune system, including esxpression of cytokines and adhesion molecules, may inhibit anti-tumor mechanisms, as well as having direct impact on angiogenesis, cell movement and metastasis. It should be noted that different kinds of gangliosides do not all act by the same mechanisms.