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author:("folly, Marie")
1.  Tumor Cell Heterogeneity in Small Cell Lung Cancer (SCLC): Phenotypical and Functional Differences Associated with Epithelial-Mesenchymal Transition (EMT) and DNA Methylation Changes 
PLoS ONE  2014;9(6):e100249.
Small Cell Lung Cancer (SCLC) is a specific subtype of lung cancer presenting as highly metastatic disease with extremely poor prognosis. Despite responding initially well to chemo- or radiotherapy, SCLC almost invariably relapses and develops resistance to chemotherapy. This is suspected to be related to tumor cell subpopulations with different characteristics resembling stem cells. Epithelial-Mesenchymal Transition (EMT) is known to play a key role in metastatic processes and in developing drug resistance. This is also true for NSCLC, but there is very little information on EMT processes in SCLC so far. SCLC, in contrast to NSCLC cell lines, grow mainly in floating cell clusters and a minor part as adherent cells. We compared these morphologically different subpopulations of SCLC cell lines for EMT and epigenetic features, detecting significant differences in the adherent subpopulations with high levels of mesenchymal markers such as Vimentin and Fibronectin and very low levels of epithelial markers like E-cadherin and Zona Occludens 1. In addition, expression of EMT-related transcription factors such as Snail/Snai1, Slug/Snai2, and Zeb1, DNA methylation patterns of the EMT hallmark genes, functional responses like migration, invasion, matrix metalloproteases secretion, and resistance to chemotherapeutic drug treatment all differed significantly between the sublines. This phenotypic variability might reflect tumor cell heterogeneity and EMT during metastasis in vivo, accompanied by the development of refractory disease in relapse. We propose that epigenetic regulation plays a key role during phenotypical and functional changes in tumor cells and might therefore provide new treatment options for SCLC patients.
doi:10.1371/journal.pone.0100249
PMCID: PMC4069054  PMID: 24959847
2.  In Situ Evolution of Virus-Specific Cytotoxic T Cell Responses in the Lung 
Journal of Virology  2013;87(20):11267-11275.
Cytotoxic T cells (CTL) play a critical role in the clearance of respiratory viral infections, but they also contribute to disease manifestations. In this study, we infected mice with a genetically modified pneumonia virus of mice (PVM) that allowed visualization of virus-specific CTL and infected cells in situ. The first virus-specific T cells entered the lung via blood vessels in the scattered foci of PVM-infected cells, which densely clustered around the bronchi at day 7 after infection. At this time, overall pulmonary virus load was maximal, but the mice showed no overt signs of disease. On days 8 to 9, T cells gained access to the infected bronchial epithelium and to the lung interstitium, which was associated with a reduction in the number of virus-infected cells within the initial clusters but could not prevent further virus spread throughout the lung tissue. Interestingly, recruitment of virus-specific CTL throughout the parenchyma was still ongoing on day 10, when the virus infection was already largely controlled. This also represented the peak of clinical disease. Thus, disease was associated with an exuberant T cell infiltration late in the course of the infection, which may be required to completely eliminate virus at residual foci of infection. PVM-induced immunopathology may thus result from the need to generate widespread T cell infiltrates to complete the elimination of virus-infected cells in a large organ like the lung. This experimental model provides the first insights into the spatiotemporal evolution of pulmonary antiviral T cell immunity in vivo.
doi:10.1128/JVI.00255-13
PMCID: PMC3807307  PMID: 23946463
3.  The Nlrp3 inflammasome regulates acute graft-versus-host disease 
The Journal of Experimental Medicine  2013;210(10):1899-1910.
Conditioning therapies before transplantation induce the release of uric acid, which triggers the NLRP3 inflammasome and IL-1β production contributing to graft-versus-host disease.
The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome–mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro–IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication.
doi:10.1084/jem.20130084
PMCID: PMC3782050  PMID: 23980097
4.  The 3' Untranslated Region of the Cyclin B mRNA Is Not Sufficient to Enhance the Synthesis of Cyclin B during a Mitotic Block in Human Cells 
PLoS ONE  2013;8(9):e74379.
Antimitotic agents are frequently used to treat solid tumors and hematologic malignancies. However, one major limitation of antimitotic approaches is mitotic slippage, which is driven by slow degradation of cyclin B during a mitotic block. The extent to which cyclin B levels decline is proposed to be governed by an equilibrium between cyclin B synthesis and degradation. It was recently shown that the 3' untranslated region (UTR) of the murine cyclin B mRNA contributes to the synthesis of cyclin B during mitosis in murine cells. Using a novel live-cell imaging-based technique allowing us to study synthesis and degradation of cyclin B simultaneously at the single cell level, we tested here the role of the human cyclin B 3'UTR in regulating cyclin B synthesis during mitosis in human cells. We observed that the cyclin B 3'UTR was not sufficient to enhance cyclin B synthesis in human U2Os, HeLa or hTERT RPE-1 cells. A better understanding of how the equilibrium of cyclin B is regulated in mitosis may contribute to the development of improved therapeutic approaches to prevent mitotic slippage in cancer cells treated with antimitotic agents.
doi:10.1371/journal.pone.0074379
PMCID: PMC3772928  PMID: 24058555
5.  Cell cycle control in acute myeloid leukemia 
Acute myeloid leukemia (AML) is the result of a multistep transforming process of hematopoietic precursor cells (HPCs) which enables them to proceed through limitless numbers of cell cycles and to become resistant to cell death. Increased proliferation renders these cells vulnerable to acquiring mutations and may favor leukemic transformation. Here, we review how deregulated cell cycle control contributes to increased proliferation in AML and favors genomic instability, a prerequisite to confer selective advantages to particular clones in order to adapt and independently proliferate in the presence of a changing microenvironment. We discuss the connection between differentiation and proliferation with regard to leukemogenesis and outline the impact of specific alterations on response to therapy. Finally, we present examples, how a better understanding of cell cycle regulation and deregulation has already led to new promising therapeutic strategies.
PMCID: PMC3433102  PMID: 22957304
Acute myeloid leukemia (AML); cell cycle; genetic instability; proliferation; differentiation
6.  Non-Invasive In Vivo Imaging of Tumor-Associated CD133/Prominin 
PLoS ONE  2010;5(12):e15605.
Background
Cancer stem cells are thought to play a pivotal role in tumor maintenance, metastasis, tumor therapy resistance and relapse. Hence, the development of methods for non-invasive in vivo detection of cancer stem cells is of great importance.
Methodology/Principal Findings
Here, we describe successful in vivo detection of CD133/prominin, a cancer stem cell surface marker for a variety of tumor entities. The CD133-specific monoclonal antibody AC133.1 was used for quantitative fluorescence-based optical imaging of mouse xenograft models based on isogenic pairs of CD133 positive and negative cell lines. A first set consisted of wild-type U251 glioblastoma cells, which do not express CD133, and lentivirally transduced CD133-overexpressing U251 cells. A second set made use of HCT116 colon carcinoma cells, which uniformly express CD133 at levels comparable to primary glioblastoma stem cells, and a CD133-negative HCT116 derivative. Not surprisingly, visualization and quantification of CD133 in overexpressing U251 xenografts was successful; more importantly, however, significant differences were also found in matched HCT116 xenograft pairs, despite the lower CD133 expression levels. The binding of i.v.-injected AC133.1 antibodies to CD133 positive, but not negative, tumor cells isolated from xenografts was confirmed by flow cytometry.
Conclusions/Significance
Taken together, our results show that non-invasive antibody-based in vivo imaging of tumor-associated CD133 is feasible and that CD133 antibody-based tumor targeting is efficient. This should facilitate developing clinically applicable cancer stem cell imaging methods and CD133 antibody-based therapeutics.
doi:10.1371/journal.pone.0015605
PMCID: PMC3004948  PMID: 21187924

Results 1-6 (6)