These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer. Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. New treatment modalities are needed for the latter group. Perhaps the most important and useful property of stem cells is that of self-renewal. Using mammary epithelial-specific mouse models targeting Trp53 and Cdkn2a, the gene coding for p16INK4a and p19ARF, we demonstrate that p53, p16INK4a, and p19ARF do not play a significant role in the limitation of normal mammary epithelium self-renewal and proliferation, whereas in the presence of the inflammatory cytokine TNF-, Trp53-/-Cdkn2a-/- mammary basal cells exhibit amplified proliferation. In addition, wild-type p53 expression also prevented FdUrd-induced DNA double-strand breaks and, unexpectedly, single-strand breaks in parental (mature) DNA. Mini Bio (1) Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. Emerson, S. G., Palsson, B. O., Clarke, M. F. INFLUENCE OF MEDIUM EXCHANGE SCHEDULES ON METABOLIC, GROWTH, AND GM-CSF SECRETION RATES OF GENETICALLY ENGINEERED NIH-3T3 CELLS. View details for DOI 10.1038/sj.onc.1207947, View details for Web of Science ID 000223998800013, View details for Web of Science ID 000223225500005. Liu, H., Bockhorn, J., Dalton, R., Nwachukwu, C., Prat, A., Yee, K., Huang, S., Swanson, K., Perou, C. M., Olopade, O. I., Clarke, M. F., Greene, G. L. MicroRNA-203 restricts the proliferation capacity of normal colon and colon cancer stem cells by regulating the expression of Tcf4. View details for Web of Science ID A1992GX27300015. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. Pulse induction of p53 alone did not affect Shep-1 cell viability, while induction of p53, followed by IR, resulted in cell death and DNA fragmentation proportional to the dose of IR and the level of p53 expression. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. A., Sim, S., Okamoto, J., Johnston, D. M., Qian, D., Zabala, M., Bueno, J., Neff, N. F., Wang, J., Shelton, A. Although cancer cell lines provide invaluable information, their biological properties often differ in crucial ways from de novo cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. We developed a new technique that replaces immunoprecipitation with a simplified chromatin fragmentation and proximity ligation step that eliminates bead purification and washing steps. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. Email: charlotte.clarke@ed.ac.uk. These data support a model in which low levels of sis gene expression in tumors contribute to the acquisition of some features of transformation but require complementation by other genes or factors to produce a fully malignant phenotype. Michael Clarke (academic) is a British academic who specialises in defence studies. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. Here, to reveal mechanisms by which different neoplastic cells generate this dominant 'don't eat me' signal, we analyse the CD47 regulatory genomic landscape. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. These data are consistent with the idea that the human T-lymphotropic virus type I LTR contains an enhancer which can activate upstream sequences in cis. Following release into G1, cells became irreversibly committed to cell death after 4 h at 32.5 degrees C. Commitment to cell death correlated with the first appearance of fragmented DNA. Our results indicate that constitutive expression of a nontruncated human c-myb cDNA can exert profound effects on erythroid differentiation and argue for a causal role of c-myb in the F-MEL differentiation process. In addition, dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. A., Clarke, M. F., Quake, S. R. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. These data demonstrate that the transcomplementation of replication-deficient adenovirus with exogenous E1 DNA leads to limited replication, and this controlled replication enhances gene transfer efficiency of adenovirus in vivo. However, deletions of more than two amino acids between this region abolished the transport of p53 into the nucleus. This is an overview of the elements and molecules involved in p53 nucleocytoplasmic transportation. On the basis of the wild-type adenovirus type 5, we have constructed a conditionally replicative adenovirus (Ad5ERE2) in which the E1a and E4 promoters have been replaced by a portion of the pS2 promoter containing two estrogen-responsive elements (EREs). These results indicate that the CSD can regulate p53 nuclear import by controlling access of the NLS to importin alpha binding. Thus, the development of proper sampling techniques or improved stem cell retention may be critical to obtain successful long-term cultures. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system. Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. One of the best candidate genes involved in conferring self-renewal capacity is Bmi-1, which has been proven to be essential for the maintenance of both normal adult hematopoietic and leukemia stem cells, as well as adult neural stem cells. Chromatin immunoprecipitation (ChIP) is a powerful assay used to probe DNA-protein interactions. Patsialou, A., Bravo-Cordero, J., Wang, Y., Liu, H., Clarke, M. F., Condeells, J. S. Deregulation of stem cell self-renewal pathways in cancer, MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Wu, A. R., Hiatt, J. Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. (2002) demonstrate that the CED-1 homolog, Slug, is a key regulator of apoptosis in the response of early hematopoietic progenitors to gamma radiation. However, inferring both the state and direction of differentiation is challenging. Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. We have designed a microfluidic device to perform sensitive ChIP analysis on low cell numbers in a rapid, automated fashion while preserving the specificity of the assay. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression. Usp16 contributes to somatic stem-cell defects in Down's syndrome. Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Recently, various new players that regulate HSC maintenance (e.g. Differentially expressed genes were used to generate a 186-gene "invasiveness" gene signature (IGS), which was evaluated for its association with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer.There was a significant association between the IGS and both overall and metastasis-free survival (P<0.001, for both) in patients with breast cancer, which was independent of established clinical and pathological variables. Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. A cell-intrinsic role for TLR2 MYD88 in intestinal and breast epithelia and oncogenesis. Thus a limiting serum component is responsible for the altered metabolic and growth rates. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. However, attempts to develop stable long-term human bone marrow cultures have been unsuccessful. Effect of ASXL1 on the stemness of colorectal cancer initiating cells. He was the founding Director of the International Policy Institute at King's College London from 2001-2005 and Head of the School of Social Science and Public Policy at KCL in 2004-05. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis. The SUVlean of residual viable tumors (4.51 +/- 1.34 [mean +/- SD]) was higher than that of mature teratoma (1.38 +/- 0.71) and necrosis or scar (1.05 +/- 0.29) (P < .05). Ryan, J. J., Danish, R., Gottlieb, C. A., Clarke, M. F. C-MYB EFFECTS ON KINETIC EVENTS DURING MEL CELL-DIFFERENTIATION. View details for Web of Science ID 000182941000008. Liu, H., Bockhorn, J., Dalton, R., Olopade, O. F., Clarke, M. F., Greene, G. L. MicroRNAs regulating breast cancer stem cells and metastasis. Since stromal cells in traditional human bone marrow cultures produce little HGFs, we have begun by asking whether local supplementation of hematopoietic growth factors via genetically engineered stromal cells might augment hematopoiesis in liquid cultures. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Some factors that regulate this process of self-renewal are conserved from fruit fly to humans. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. Lobo, N. A., Zabala, M., Qian, D., Clarke, M. F. Serially transplantable mammary epithelial cells express the Thy-1 antigen. This functional subset of cancer cells is operationally defined as the "cancer stem cell" (CSC) subset. Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. We screened for genetic polymorphisms that were linked to differences between mouse strains in the numbers of long-term reconstituting HSCs or restricted progenitors in the bone marrow. Here we report that Usp16, a negative regulator of Bmi1/PRC1 function, modulates the Wnt pathway in mammary epithelia, primary human fibroblasts and MEFs, affecting their expansion and self-renewal potential. Heights. We developed an immunodeficient mouse model to test the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. Fifteen (52%) received both transplants. Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. However, KITLG-knockdown DLD1 cells formed smaller xenograft tumors than control cells. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells. School of Civil Engineering +61 7 336 56464. william.clarke@uq.edu.au. There will be a great deal of national soul-searching as the tragedy in Afghanistan unfolds before us. Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. At a meeting of the Translation Research Program of the Radiation Therapy Oncology Group held in early 2008, attendees focused on updating the current state of knowledge in cancer stem cell research and discussing ways in which this knowledge can be translated into clinical use across all disease sites. LDV infects specifically mouse macrophages and alters immune system and tumor phenotype. Mutagenesis analysis demonstrated that a single amino acid mutation of Lys-305 (mt p53) caused cytoplasmic sequestration of the p53 protein in the MCF-7 and RKO cells, whereas the fusion protein was distributed in both the cytoplasm and the nucleus of SAOS-2 cells. Investigator:Michael Clarke (CI) Rural Industries Research & Development Corporation, 2016, $130,500 Development of honeybee products from a biodiversity hotspot Katherine Hammer, Connie Locher, Michael Clarke (CI) MS Research Australia, 2014, $180,000 Project Title: Vitamin D metabolites and risk of multiple sclerosis in the Ausimmune Study CD137 activation, which was dependent on NK cell expression of the FcRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. View details for Web of Science ID 000166430900009. In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. Professor. Under these conditions, the cultures produced as many cells as were inoculated every 2 weeks and led to a greater than 2.5-fold expansion in terms of the number of nonadherent cells produced over a 6- to 8-week period. 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