Person: Kim, Carla
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Carla
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Kim, Carla
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Publication Lung Stem Cell Self-Renewal Relies on BMI1-Dependent Control of Expression at Imprinted Loci(Elsevier BV, 2011-09-02) Zacharek, Sima J.; Fillmore, Christine M.; Lau, Allison N.; Gludish, David W.; Chou, Alan; Ho, Joshua W.K.; Zamponi, Raffaella; Gazit, Roi; Bock, Christoph; Jäger, Natalie; Smith, Zachary; Kim, Tae-min; Saunders, Arven H.; Wong, Janice; Lee, Joo-Hyeon; Roach, Rebecca R.; Rossi, Derrick; Meissner, Alexander; Gimelbrant, Alexander; Park, Peter; Kim, CarlaBmi1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally- or paternally-inherited allele, are known to regulate developmental processes but their role in adult cells remains a fundamental question. Many imprinted genes were de-repressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that Bmi1-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells.Publication p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis(American Association for the Advancement of Science (AAAS), 2009-12-17) Kirsch, David G.; Santiago, Philip M.; Di Tomaso, Emmanuelle; Sullivan, Julie M.; Hou, Wu-Shiun; Dayton, Talya; Jeffords, Laura B.; Sodha, Pooja; Mercer, Kim; Cohen, Rhianna; Takeushi, Osamu; Takeuchi, Osamu; Korsmeyer, Stanley J.; Bronson, Roderick; Kim, Carla; Haigis, Kevin; Jain, Rakesh; Jacks, TylerAcute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells mediating the GI syndrome are derived from the epithelium or endothelium, and whether the target cells die by apoptosis or other mechanisms, are controversial issues. Studying mouse models, we found that selective deletion of the pro-apoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after subtotal body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by death of GI epithelial cells by a mechanism that is regulated by p53 but independent of apoptosis.Publication Commentary: Sca-1 and Cells of the Lung: A Matter of Different Sorts(Wiley, 2009-03) Raiser, David M.; Kim, CarlaIn two separate papers published in this issue, Teisanu et al. and McQualter et al. report the use of flow cytometry and cell sorting to identify putative bronchiolar stem cells that are low in expression for the cell surface marker Sca-1 yet negative for CD34, and a mesenchymal, fibroblastic progenitor cell population from the lung that is positive for Sca-1, respectively. At first glance, these studies may seem to suggest that Sca-1 and CD34 are not markers of an epithelial stem cell population in the lung, as we previously determined in studies that identified bronchioalveolar stem cells (BASCs), and may also appear to contradict each other. However, here we point to evidence that the findings of these three studies are not mutually exclusive, and rather, that the different cell isolation and culturing protocols used in these studies have allowed for the identification of unique pulmonary cell populations. Rather than discounting previous work on BASCs, these studies reveal the existence of new methods and new cell types which will be interesting to use in future functional tests for their importance in lung biology and lung disease.Publication Isolation and Characterization of Distal Lung Progenitor Cells(Humana Press, 2012-04-14) Driscoll, Barbara; Kikuchi, Alex; Lau, Allison N.; Lee, Jooeun; Reddy, Raghava; Jesudason, Edwin; Kim, Carla; Warburton, DavidThe majority of epithelial cells in the distal lung of rodents and humans are quiescent in vivo, yet certain cell populations retain an intrinsic capacity to proliferate and differentiate in response to lung injury or in appropriate culture settings, thus giving them properties of stem/progenitor cells. Here, we describe the isolation of two such populations from adult mouse lung: alveolar epithelial type 2 cells (AEC2), which can generate alveolar epithelial type 1 cells, and bronchioalveolar stem cells (BASCs), which in culture can reproduce themselves, as well as generate a small number of other distal lung epithelial cell types. These primary epithelial cells are typically isolated using enzyme digestion, mechanical disruption, and serial filtration. AEC2 and BASCs are distinguished from other distal lung cells by expression of specific markers as detected by fluorescence-activated cell sorting, immunohistochemistry, or a combination of both of these techniques.Publication Primary Tumor Genotype Is an Important Determinant in Identification of Lung Cancer Propagating Cells(Elsevier BV, 2010-07-02) Curtis, Stephen J.; Sinkevicius, Kerstin W.; Li, Danan; Lau, Allison N.; Roach, Rebecca R.; Zamponi, Raffaella; Woolfenden, Amber E.; Kirsch, David G.; Wong, Kwok-Kin; Kim, CarlaSuccessful cancer therapy requires the elimination or incapacitation of all tumor cells capable of regenerating a tumor. Therapeutic advances therefore necessitate the characterization of the cells that are able to propagate a tumor in vivo. We show an important link between tumor genotype and isolation of tumor-propagating cells (TPCs). Three mouse models of the most common form of human lung cancer each had TPCs with a unique cell surface phenotype. The cell surface marker Sca1 did not enrich for TPCs in tumors initiated with oncogenic Kras, and only Sca1-negative cells propagated EGFR mutant tumors. In contrast, Sca1-positive cells were enriched for tumor-propagating activity in Kras tumors with p53 deficiency. Primary tumors that differ in genotype at just one locus can therefore have tumor-propagating cell populations with distinct markers. Our studies show that the genotype of tumor samples must be considered in studies to identify, characterize, and target tumor-propagating cells. Summary Depending on the tumor initiating genetic event in three tractable mouse models of lung adenocarcinoma, the surface maker Sca1 had variable success in identifying cells with tumor-propagating activity. These findings uncover the impact that tumor genotype can have on the phenotype of tumor-propagating cells, which may have important therapeutic significance. Highlights -identification of the first lung tumor-propagating cell population -lung cancers of different genotype have tumor-propagating cells with distinct markers -tumor samples should be separated by genotype to study tumor-propagating cellsPublication A Genetic Screen Identifies an LKB1–MARK Signalling Axis Controlling the Hippo–YAP Pathway(Springer Nature, 2014-01) Mohseni, Morvarid; Sun, Jianlong; Lau, Allison; Curtis, Stephen; Goldsmith, Jeffrey; Fox, Victor; Wei, Chongjuan; Frazier, Marsha; Samson, Owen; Wong, Kwok-Kim; Kim, Carla; Camargo, FernandoThe Hippo-YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size. To identify components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies. In addition, our findings provide insight into upstream signals of the Hippo-YAP signalling cascade.Publication EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors(2014) Fillmore, Christine M.; Xu, Chunxiao; Desai, Pooja T.; Berry, Joanne M.; Rowbotham, Samuel; Lin, Yi-Jang; Zhang, Haikuo; Marquez, Victor E.; Hammerman, Peter S.; Wong, Kwok-Kin; Kim, CarlaSUMMARY Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide1. Chemotherapies such as the topoisomerase II inhibitor (TopoIIi) etoposide effectively reduce disease in a minority of NSCLC patients2,3; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention4. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the Polycomb Repressive Complex 2 (PRC2) is well known to tri-methylate Histone H3 at lysine 27 (H3K27me3) and elicit gene silencing5. Here, we demonstrate that EZH2 inhibition (EZH2i) had differential effects on TopoIIi response of NSCLCs in vitro and in vivo. EGFR and BRG1 mutations were genetic biomarkers that predicted enhanced sensitivity to TopoIIi in response to EZH2i. BRG1 loss-of-function mutant tumors responded to EZH2i with increased S phase, anaphase bridging, apoptosis, and TopoIIi sensitivity. Conversely, EGFR and BRG1 wild-type tumors up-regulated BRG1 in response to EZH2i and ultimately became more resistant to TopoIIi. EGFR gain-of-function mutant tumors were also sensitive to dual EZH2i and TopoIIi, due to genetic antagonism between EGFR and BRG1. These findings suggest an exciting opportunity for precision medicine in the genetically complex disease of NSCLC.Publication Intersections of lung progenitor cells, lung disease and lung cancer(2018) Kim, CarlaThe use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today’s better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials.Publication Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6(Cell Press, 2017) Lee, Joo-Hyeon; Tammela, Tuomas; Hofree, Matan; Choi, Jinwook; Marjanovic, Nemanja Despot; Han, Seungmin; Canner, David; Wu, Katherine; Paschini, Margherita; Bhang, Dong Ha; Jacks, Tyler; Regev, Aviv; Kim, CarlaSummary The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.Publication Direct Recruitment of Polycomb Repressive Complex 1 to Chromatin by Core Binding Transcription Factors(Elsevier BV, 2012) Yu, Ming; Mazor, Tali; Huang, Hui; Huang, Hsuan-Ting; Kathrein, Katie L.; Woo, Andrew; Chouinard, Candace R.; Labadorf, Adam; Akie, Thomas E.; Moran, Tyler B.; Xie, Huafeng; Zacharek, Sima; Taniuchi, Ichiro; Roeder, Robert G.; Kim, Carla; Zon, Leonard; Fraenkel, Ernest; Cantor, AlanPolycomb repressive complexes (PRCs) play key roles in developmental epigenetic regulation. Yet the mechanisms that target PRCs to specific loci in mammalian cells remain incompletely understood. In this study we show that Bmi1, a core component of Polycomb Repressive Complex 1 (PRC1), binds directly to the Runx1/CBFβ transcription factor complex. Genome-wide studies in megakaryocytic cells demonstrate significant chromatin occupancy overlap between the PRC1 core component Ring1b and Runx1/CBFβ and functional regulation of a considerable fraction of commonly bound genes. Bmi1/Ring1b and Runx1/CBFβ deficiencies generate partial phenocopies of one another in vivo. We also show that Ring1b occupies key Runx1 binding sites in primary murine thymocytes and that this occurs via PRC2-independent mechanisms. Genetic depletion of Runx1 results in reduced Ring1b binding at these sites in vivo. These findings provide evidence for site-specific PRC1 chromatin recruitment by core binding transcription factors in mammalian cells.
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