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  1. Article ; Online: CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer.

    Gao, Shanshan / Soares, Fraser / Wang, Shiyan / Wong, Chi Chun / Chen, Huarong / Yang, Zhenjie / Liu, Weixin / Go, Minnie Y Y / Ahmed, Musaddeque / Zeng, Yong / O'Brien, Catherine Adell / Sung, Joseph J Y / He, Housheng Hansen / Yu, Jun

    Oncogene

    2021  Volume 40, Issue 48, Page(s) 6601–6613

    Abstract: Cancer stem cells (CSCs) are responsible for tumor progression, recurrence, and drug resistance. To identify genetic vulnerabilities of colon cancer, we performed targeted CRISPR dropout screens comprising 657 Drugbank targets and 317 epigenetic ... ...

    Abstract Cancer stem cells (CSCs) are responsible for tumor progression, recurrence, and drug resistance. To identify genetic vulnerabilities of colon cancer, we performed targeted CRISPR dropout screens comprising 657 Drugbank targets and 317 epigenetic regulators on two patient-derived colon CSC-enriched spheroids. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells yielded therapeutic candidates. We unraveled 44 essential genes for colon CSC-enriched spheroids propagation, including key cholesterol biosynthetic genes (HMGCR, FDPS, and GGPS1). Cholesterol biosynthesis was induced in colon cancer tissues, especially CSC-enriched spheroids. The genetic and pharmacological inhibition of HMGCR/FDPS impaired self-renewal capacity and tumorigenic potential of the spheroid models in vitro and in vivo. Mechanistically, HMGCR or FDPS depletion impaired cancer stemness characteristics by activating TGF-β signaling, which in turn downregulated expression of inhibitors of differentiation (ID) proteins, key regulators of cancer stemness. Cholesterol and geranylgeranyl diphosphate (GGPP) rescued the growth inhibitory and signaling effect of HMGCR/FDPS blockade, implying a direct role of these metabolites in modulating stemness. Finally, cholesterol biosynthesis inhibitors and 5-FU demonstrated antitumor synergy in colon CSC-enriched spheroids, tumor organoids, and xenografts. Taken together, our study unravels novel genetic vulnerabilities of colon CSC-enriched spheroids and suggests cholesterol biosynthesis as a potential target in conjunction with traditional chemotherapy for colon cancer treatment.
    MeSH term(s) Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis ; CRISPR-Cas Systems ; Cell Proliferation ; Cholesterol/biosynthesis ; Cholesterol/chemistry ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/genetics ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Dimethylallyltranstransferase/antagonists & inhibitors ; Drug Resistance, Neoplasm/drug effects ; Farnesyltranstransferase/antagonists & inhibitors ; Fluorouracil/administration & dosage ; Geranyltranstransferase/antagonists & inhibitors ; Humans ; Lovastatin/administration & dosage ; Male ; Mice ; Mice, Nude ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Zoledronic Acid/administration & dosage
    Chemical Substances Zoledronic Acid (6XC1PAD3KF) ; Cholesterol (97C5T2UQ7J) ; Lovastatin (9LHU78OQFD) ; Dimethylallyltranstransferase (EC 2.5.1.1) ; Geranyltranstransferase (EC 2.5.1.10) ; Farnesyltranstransferase (EC 2.5.1.29) ; GGPS1 protein, human (EC 2.5.1.29) ; Fluorouracil (U3P01618RT)
    Language English
    Publishing date 2021-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-021-01882-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cancer stem cells in solid tumors: an overview.

    O'Brien, Catherine Adell / Kreso, Antonija / Dick, John E

    Seminars in radiation oncology

    2009  Volume 19, Issue 2, Page(s) 71–77

    Abstract: It has long been appreciated that significant functional and morphologic heterogeneity can exist within the individual cells that comprise a tumor. Increasing evidence indicates that many solid tumors are organized in a hierarchical manner in which tumor ...

    Abstract It has long been appreciated that significant functional and morphologic heterogeneity can exist within the individual cells that comprise a tumor. Increasing evidence indicates that many solid tumors are organized in a hierarchical manner in which tumor growth is driven by a small subset of cancer stem cells (CSCs) or tumor-initiating cells. Although these cells represent a small percentage of the overall tumor population, they are the only cells capable of initiating and driving tumor growth. Emerging evidence indicates that these cells are also resistant to chemotherapy and radiation therapy, which has led to much speculation and interest surrounding the potential clinical applicability of CSCs.
    MeSH term(s) Animals ; Humans ; Mice ; Neoplasms/drug therapy ; Neoplasms/pathology ; Neoplasms/radiotherapy ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/pathology ; Neoplastic Stem Cells/radiation effects
    Language English
    Publishing date 2009-04
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1146999-7
    ISSN 1532-9461 ; 1053-4296
    ISSN (online) 1532-9461
    ISSN 1053-4296
    DOI 10.1016/j.semradonc.2008.11.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3654: Show issues Location:
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  3. Article ; Online: Colon cancer stem cells.

    Kreso, Antonija / O'Brien, Catherine Adell

    Current protocols in stem cell biology

    2008  Volume Chapter 3, Page(s) Unit 3.1

    Abstract: This unit describes protocols for working with colon cancer stem cells. To work with these cells one must start by generating single-cell suspensions from human colon cancer tissue. These cell suspensions are sorted using flow cytometry-assisted cell ... ...

    Abstract This unit describes protocols for working with colon cancer stem cells. To work with these cells one must start by generating single-cell suspensions from human colon cancer tissue. These cell suspensions are sorted using flow cytometry-assisted cell sorting to fractionate the cells into tumor-initiating and nontumor-initiating subsets. Once the cells have been fractionated, they must be functionally tested to determine tumor-forming capacity, the gold standard being the in vivo xenograft assay. Methods have also been developed to grow these cells in vitro in a sphere-forming assay. This unit will describe how to isolate and functionally test colon cancer stem cells, as well as provide advice on the potential challenges of the research.
    MeSH term(s) Animals ; Cell Culture Techniques/methods ; Cell Separation/methods ; Colonic Neoplasms/pathology ; Humans ; Neoplastic Stem Cells/cytology ; Spheroids, Cellular/cytology
    Language English
    Publishing date 2008-11
    Publishing country United States
    Document type Journal Article
    ISSN 1938-8969
    ISSN (online) 1938-8969
    DOI 10.1002/9780470151808.sc0301s7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Cancer stem cells and self-renewal.

    O'Brien, Catherine Adell / Kreso, Antonija / Jamieson, Catriona H M

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2010  Volume 16, Issue 12, Page(s) 3113–3120

    Abstract: The cancer stem cell (CSC) or cancer-initiating cancer (C-IC) model has garnered considerable attention over the past several years since Dick and colleagues published a seminal report showing that a hierarchy exists among leukemic cells. In more recent ... ...

    Abstract The cancer stem cell (CSC) or cancer-initiating cancer (C-IC) model has garnered considerable attention over the past several years since Dick and colleagues published a seminal report showing that a hierarchy exists among leukemic cells. In more recent years, a similar hierarchical organization, at the apex of which exists the CSC, has been identified in a variety of solid tumors. Human CSCs are defined by their ability to: (i) generate a xenograft that histologically resembles the parent tumor from which it was derived, (ii) be serially transplanted in a xenograft assay thereby showing the ability to self-renew (regenerate), and (iii) generate daughter cells that possess some proliferative capacity but are unable to initiate or maintain the cancer because they lack intrinsic regenerative potential. The emerging complexity of the CSC phenotype and function is at times daunting and has led to some confusion in the field. However, at its core, the CSC model is about identifying and characterizing the cancer cells that possess the greatest capacity to regenerate all aspects of the tumor. It is becoming clear that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and CSC maintenance will lead to a better understanding of the mechanisms driving tumor growth. This review will address some of the main controversies in the CSC field and emphasize the importance of focusing first and foremost on the defining feature of CSCs: dysregulated self-renewal capacity.
    MeSH term(s) Animals ; Cell Proliferation ; Disease Models, Animal ; Drug Delivery Systems ; Embryonic Development ; Humans ; Mice ; Neoplasm Transplantation ; Neoplasms/drug therapy ; Neoplasms/pathology ; Neoplastic Stem Cells/pathology ; Signal Transduction/drug effects
    Language English
    Publishing date 2010-06-15
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-09-2824
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4223: Show issues Location:
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  5. Article: Active and passive commuting to school: influences on affect in primary school children.

    Hulley, Angela / Bentley, Nick / Clough, Catherine / Fishlock, Adelle / Morrell, Frances / O'Brien, James / Radmore, Joseph

    Research quarterly for exercise and sport

    2008  Volume 79, Issue 4, Page(s) 525–534

    Abstract: Active commuting among school children is being encouraged for physical and environmental reasons, but little is known about its influence on affect. The aim of this study was to test the hypothesis that children who walk further to school experience ... ...

    Abstract Active commuting among school children is being encouraged for physical and environmental reasons, but little is known about its influence on affect. The aim of this study was to test the hypothesis that children who walk further to school experience increased arousal and affective valence compared with children who walk a short distance. This was assessed with the children's feeling scale (CFS) and children's felt arousal scale (CFAS). Distance walked to school and affective change between home and school were assessed over a 2-week period in 99 children between 5 and 10 years of age. Home to school differences in CFS and CFAS scores were compared in children who walked a short (100-300 m); medium (301-500 m), and long distance (over 500 m). Although differences were not always statistically significant, there was evidence that the children who walked further reported a greater increase in their CFAS scores between home and school (average eta2 = .08, range: .01-.15) and, to a lesser extent, in their CFS scores (eta2 = .04, range: .002-.06). Further research is needed to explore whether there is an optimum walking distance and the contribution of other factors, especially social contacts during commuting, the environment, and the weather.
    MeSH term(s) Affect ; Analysis of Variance ; Arousal ; Automobile Driving ; Chi-Square Distribution ; Child ; Child, Preschool ; England ; Female ; Humans ; Male ; Pilot Projects ; Psychiatric Status Rating Scales ; Surveys and Questionnaires ; Walking/physiology ; Weather
    Language English
    Publishing date 2008-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 225654-x
    ISSN 2168-3824 ; 0270-1367
    ISSN (online) 2168-3824
    ISSN 0270-1367
    DOI 10.1080/02701367.2008.10599519
    Database MEDical Literature Analysis and Retrieval System OnLINE

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