bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B26: Centriole amplification during mammalian multiciliated cell development reveals a novel centrosome asymmetry
Authors: Jord Adel Al , Spassky Nathalie , Meunier Alice 
Published: May 2016

Abstract
The centrosome comprises a mother and a daughter centriole, both regarded as equivalent in their ability to form new centrioles. Their symmetric duplication during the cell cycle is crucial for proper genetic partitioning between the daughter cells. In multiciliated cells, hundreds of centrioles are thought to appear de novo, i.e. independently from the centrosome, to nucleate the same number of motile cilia and propel physiological fluids. The origin of these centrioles remains unknown. Here we provide the cellular mechanism driving large-scale centriole production in multiciliated cells and identify the daughter centriole of the centrosome as the nucleation point for 95% of the new centrioles. Using live imaging combined with correlative super-resolution light and electron microscopy microscopy, we show that centriole amplification proceeds through a recurrent mechanism whereby the daughter centriole concomitantly generates the new centrioles and their cytoplasmic shuttles known as deuterosomes. By revealing this novel centrosome cycle, our work challenges the postulate that large-scale centriole production is a de novo mechanism in mammalian cells. In addition, it uncovers a fundamental asymmetry between mother and daughter centrioles in the control of centriole biogenesis and number. These results may have critical implications in the understanding of the etiology of cilia-related diseases, brain defects, and tumor formation.
Citation Format: Adel Al Jord, Nathalie Spassky, Alice Meunier. Centriole amplification during mammalian multiciliated cell development reveals a novel centrosome asymmetry. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B26.
Abstract B29: Snail regulates extracellular matrix-mediated VEGFR3 expression in developmental and tumor angiogenesis
Authors: Park Jeong Ae , Lee Ho-Young , Kwon Young-Guen 
Published: May 2016

Abstract
Snail family is a zinc finger transcription factor and involved in epithelial branching morphogenesis and EMT by altering the ability of polarity, motility, and adhesion. The expression of Snail family in developing and tumor vessels has been suggested, however, the precise expression pattern and cellular function of Snail remain to be unclear. We identified Snail as an angiogenic regulator through inducing VEGFR3 under extracellular matrix (ECM)-meditated signalings. Snail was upregulated in the postnatally developing retinal endothelial cells (ECs) and in the vessels lining ductal breast tumors. In vitro endothelial sprouting assay indicated that knockdown or ectopic expression of Snail impaired EC sprouting on ECM. Moreover, Snail colocalized with VEGFR3 and upregulated VEGFR3 mRNA by cooperating with early growth response protein-1 in ECs. In the developing vessel model, intraperitoneal injection with stable Snail siRNA in postnatal mice demonstrated that Snail loss attenuated the formation of the vascular plexus not only by impairing vertical sprouting vessels but also by downregulating VEGFR3. Furthermore, in MMTV-PyMT breast tumors, Snail was strongly expressed in endothelial vessels around ductal breast tumors along with VEGFR3 expression. These data demonstrate that Snail contributes to vascular morphogenesis by upregulating VEGFR3. ECM-Snail-VEGFR3 axis may play crucial roles in disorganized vascular network in solid tumors.
Citation Format: Jeong Ae Park, Ho-Young Lee, Young-Guen Kwon. Snail regulates extracellular matrix-mediated VEGFR3 expression in developmental and tumor angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B29.
Abstract B40: Effect of Sasa quelpaertensis leaf extracts on the gut microbiota in dextran sodium sulfate-induced colitis in mice
Authors: Yeom Yiseul , Kim Yuri 
Published: May 2016

Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are chronic inflammatory disorders of gastrointestinal tract. Although the etiology of IBD is not clear, it may be associated with genetics and lifestyle factors, diet and gut microbiome. In particular, the imbalance among the immune system and gut microbiota and diet may play a key role in developing IBD. Sasa quelpaertensis leaves have shown anti-inflammatory and anticarcinogenic effects, although the effect of these leaves on gut microbiota in colitis remains unclear. The present study hypothesized that Sasa quelpaertensis leaves extract (SQE) exerts a protective effect against a dextran sulfate sodium (DSS)-induced colitis in mice through modulating gut microbiota. SQE (100 mg/kg or 300 mg/kg b.w.) were pre-treated to mice by gavage two weeks before inflammation which was induced by 2.5% DSS in drinking water for two cycles of each 7 days and tap water for 7 days was provided between DSS treatment. Disease activity index (DAI), colon length were measured and microbiota were analyzed using pyrosequencing in fecal samples. SQE attenuated the severity of DSS-induced colitis. In addition, SQE group had more Firmicutes in phylum level compared to DSS group, Bacteroidetes/Firmicutes ratio of DSS group was significantly higher than control and SQE groups. Furthermore, major microbiota compositions were different in class, family, genus, and species level among control, DSS control, and SQE group. Estimator of community richness, the OTUs, in DSS group tended to lower compared with SQE groups and estimator of evenness and diversity, Chao-1, ACE, Shannon, NP Simpson, were significantly lower in DSS group compared with SQE groups (p&lt;0.05). Our results suggest that SQE affects microbiome composition and number change on DSS-induced colitis mouse model, these change in the microbiome may be beneficial and can be an effective strategy for prevention of IBD (This work was conducted with the support of the Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ009777) Rural Development Administration, Republic of Korea, and the Brain Korea 21 Plus (Project No. 22A20130012143).
Citation Format: Yiseul Yeom, Yuri Kim. Effect of Sasa quelpaertensis leaf extracts on the gut microbiota in dextran sodium sulfate-induced colitis in mice. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B40.
Abstract IA05: Polycomb repressive complex-2 is a barrier to Kras-driven inflammation and epithelial-mesenchymal transition in non-small cell lung cancer
Authors: Serresi Michela , Gargiulo Gaetano , Proost Nathalie , Siteur Bjorn , Cesaroni Matteo , Koppens Martijn , Xie Huafeng , Sutherland Kate , Hulsman Danielle , Citterio Elisabetta , Orkin Stuart , Berns Anton , Lohuizen Maarten van 
Published: May 2016

Abstract
Polycomb repressive complexes (PRC) are frequently implicated in human cancer acting either as oncogenes or tumor suppressors. Here we show that PRC2 is a critical regulator of Kras-driven non-small-cell lung cancer (NSCLC) progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances Kras-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell autonomous epithelial-to- mesenchymal transition (EMT) program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt-signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application.
Citation Format: Michela Serresi, Gaetano Gargiulo, Nathalie Proost, Bjorn Siteur, Matteo Cesaroni, Martijn Koppens, Huafeng Xie, Kate Sutherland, Danielle Hulsman, Elisabetta Citterio, Stuart Orkin, Anton Berns, Maarten van Lohuizen. Polycomb repressive complex-2 is a barrier to Kras-driven inflammation and epithelial-mesenchymal transition in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA05.
Abstract IA06: Stem cells in mammalian epidermis
Authors: Watt Fiona M. 
Published: May 2016

Abstract
Multiple epidermal stem cell subpopulations in adult mouse skin have been identified over the last decade. Although they are all competent to give rise to all the different epidermal lineages following transplantation, wounding or genetic modification, under steady state conditions they maintain the epidermis in a compartmentalized manner. Stem cells in the lower hair follicle express LGR5, while stem cells in the upper follicle express LGR6 and cells in the junctional zone express LRIG1. In addition, a subset of stem cells in the interfollicular epidermis expresses LGR6. In my presentation I will discuss the consequences of selectively expressing activated beta-catenin in the different epidermal stem cell populations.
Citation Format: Fiona M. Watt. Stem cells in mammalian epidermis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA06.
Abstract IA10: Notch signaling and cancer
Authors: Junker Fabian , Lehal Rajwinder , Frimantas Viktoras , Bornhauser Beat C. , Bourquin Jean-Pierre , Koch Ute , Radtke Freddy 
Published: May 2016

Abstract
Cancer can be seen as disease of perturbed self-renewal. In the last decades it became clear that many of the signaling pathways known to be important during embryonic development also play important roles in regulating self-renewing tissues. Deregulation of the self-renewal process results in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis all of which are hallmarks of cancer. The major question is how do these deregulated signaling cascades mechanistically contribute to cancer and are they suitable for targeting therapy?
The Notch pathway is one such cascade required for normal stem cell maintenance and development of different organs. Over activation of this pathway due to mutations in the Notch receptor are found in more than 50% of human T-cell leukemia and deregulated Notch signaling has been shown to promote tumor progression of various organs. The oncogenic mediators of aberrant Notch function in T-ALL and other Notch-driven cancers appear to be manifold and complex. The modulatory function of individual miRNAs in Notch driven T-ALLs has recently been established. However, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. We used conditional and inducible genetic loss of function approaches to show that development and maintenance of Notch-driven T-ALL is dependent on Dicer1 function. Lineage tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4.
Moreover, we will report on the identification of a novel small molecule inhibitor (CB103) that blocks Notch signaling by interfering with the transcriptional activation complex. The compound CB103 has shown remarkable ability to block Notch signaling in human cancer cell lines as well as primary human T-ALL cells, thus abrogating their proliferative properties. In addition, compound CB103 exhibit in vivo activity as demonstrated by its ability to impinge upon Notch dependent developmental processes and by impeding tumor growth in xenograft models of human leukemia and breast cancer.
Citation Format: Fabian Junker, Rajwinder Lehal, Viktoras Frimantas, Beat C. Bornhauser, Jean-Pierre Bourquin, Ute Koch, Freddy Radtke. Notch signaling and cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA10.
Abstract IA16: SWI/SNF (BAF) complex mutations in cancer
Authors: Roberts Charles W. M. 
Published: May 2016

Abstract
Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription.
My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented.
Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA16.
Abstract A14: Role of mitochondrial folate metabolism in cancer cell growth and proliferation
Authors: Ducker Gregory S. , Esposito Mark B. , Kang Yibin , Rabinowitz Joshua D. 
Published: May 2016

Abstract
Introduction: Increased expression of mitochondrial folate enzymes, especially mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2), is one of the most consistent gene expression changes in human tumors. Folate metabolism is a major consumer of serine, the primary donor of one-carbon units. One-carbon units generated from serine in the mitochondrion can be transferred into the cytosol as formate for use in cytosolic biosynthesis. Using genetics and quantitative metabolic methods, we examined the role of mitochondrial folate metabolism in cell growth in culture and in xenografted tumors.
Methods: Using CRISPR-Cas9 technology, we created deletion mutant cell lines for enzymes in folate metabolism. Cells deleted for MTHFD2 were grown as xenografts in mice. Metabolites from cultured cells and xenografts were analyzed by liquid chromatography mass spectrometry (LC-MS).
Results: Mitochondrial folate metabolism is not required for growth in standard tissue culture media conditions. The reversal of the direction of cytosolic one-carbon flux enables rapid cell growth of MTHFD2 mutants albeit with metabolic hallmarks of 10-formyltetrahydrofolate deficiency. However, MTHFD2 deletion cells are, as previously shown, glycine auxotrophs and under those conditions show metabolic hallmarks of oxidative stress. Exogenous formate rescues the 10-formyltetrahydrofolate deficiency but not the glycine auxotrophy. Additionally, we find these cells are also growth impaired under low serine conditions. Importantly, compared to paired wild type tumors, growth of MTHFD2 mutant subcutaneous xenografts was markedly reduced.
Conclusions: Mitochondrial folate metabolism is conditionally required for rapid cell growth. High expression of mitochondrial folate genes in cancer may function to meet requirements for one-carbon units, glycine, or redox homeostasis under nutrient stress.
Citation Format: Gregory S. Ducker, Mark B. Esposito, Yibin Kang, Joshua D. Rabinowitz. Role of mitochondrial folate metabolism in cancer cell growth and proliferation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A14.
Abstract A17: Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth
Authors: Jin Lingtao , Li Dan , Alesi Gina , Fan Jun , Kang Hee-Bum , Zhou Lu , Boggon Titus , Jin Peng , Egnatchik Robert , DeBerardinis Ralph , Magliocca Kelly , He Chuan , Arellano Martha , Khoury Hanna , Shin Dong , Khuri Fadlo , Kang Sumin 
Published: May 2016

Abstract
How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1), commonly upregulated in human cancers, is predominantly important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate (a-KG) and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a ROS scavenging enzyme glutathione peroxidase 1 (GPx1) to regulate redox homeostasis, which provides a proliferative advantage to cancer cells and tumor growth. Our findings not only provide novel insights into understanding of the role of glutaminolysis in redox homeostasis but also suggest a novel signaling function of fumarate that regulates GPx1, allowing additional crosstalk between glutaminolysis, TCA cycle and redox status. Targeting GDH1 by shRNA or a newly identified small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth. Thus, our findings provide proof-of-principle suggesting GDH1 as a promising therapeutic target in the treatment of human cancers associated with elevated glutamine metabolism.
Citation Format: Lingtao Jin, Dan Li, Gina Alesi, Jun Fan, Hee-Bum Kang, Lu Zhou, Titus Boggon, Peng Jin, Robert Egnatchik, Ralph DeBerardinis, Kelly Magliocca, Chuan He, Martha Arellano, Hanna Khoury, Dong Shin, Fadlo Khuri, Sumin Kang. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A17.
Abstract A48: Metabolic adaptations to serine starvation
Authors: Labuschagne Christiaan F. , Maddocks Oliver D.K. , Vousden Karen H. 
Published: May 2016

Abstract
Folate dependent one carbon metabolism is essential for cell growth and proliferation and provides building blocks for nucleotide synthesis, NADPH production and methylation of DNA, protein and lipids. The non-essential amino acid serine is an important one-carbon donor and although cells can make serine, many cancer cell lines that have not up-regulated the de novo serine synthesis pathway are dependent on exogenous serine for optimal growth. Indeed, many rapidly proliferating cancer cells take up high quantities of serine from the external environment to support one-carbon metabolism. Using a genetically engineered mouse tumor model, we have now also shown that intestinal tumors in vivo take up more serine than surrounding normal tissue.
Through metabolic analysis and by measuring enzyme expression, we investigated how cancer cells adapt to serine starvation. We have found that cells prioritize different metabolic processes during serine starvation, favouring NADPH production over anabolic pathways such as nucleotide synthesis.
Citation Format: Christiaan F. Labuschagne, Oliver D.K. Maddocks, Karen H. Vousden. Metabolic adaptations to serine starvation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A48.
Abstract A53: Antiproliferative, antiangiogenic and proapoptotic actions qualify Nigella sativa as taxane therapy adjuvant in ovarian cancer
Authors: Mathur Rajani , Tiwari Mukesh 
Published: May 2016

Abstract
Taxane {Docetaxel (DTX), Paclitaxel (PTX)} based standard chemotherapeutic management of ovarian cancer faces the limitations of resistant phenotype and systemic toxicity. To explore potential agents for adjuvant drug therapy, ethanolic extract of seeds of medicinal plant-Nigella sativa (NS) and Thymoquinone (THM), an isolated volatile oil from its seeds are investigated here against Human Epithelial Ovarian Cancer cell line (SKOV3).
Using SKOV3 cells, grown and maintained under standardised protocols of cell culture, the anti-proliferative effect of DTX, PTX, NS and THM was evaluated individually at 4µM, 4µM, 100µg and 100µM respectively. Combination of DTX(2µM)/PTX(2µM)+NS(50µg)/THM(50µM) were evaluated at sub IC50 for anti-proliferative activity and putative mechanistic basis (IL-8, TNFα, VEGF, Bcl2, Bax).
Here, IC50 value of DTX, PTX, NS and THM is reported as 4.7µM, 5.3µM, 71.8µg and 0.11pM, respectively. Cytotoxicity of DTX+NS/THM and PTX+NS/THM was 54.22,59.85, 55.5 and 60.36%, respectively that was greater than either DTX , PTX, NS or THM at 48.24, 47.18, 59.4 and 48.35% respectively.
Following 24 hr treatment, DTX, PTX, NS, THM and DTX/PTX+NS/THM significantly induced levels of IL-8 and pro-apoptotic protein Bax, but, reduced secretion of TNF-α, VEGF and anti-apoptotic protein Bcl-2 vs control.
Agents that interact synergistically or additively with chemotherapeutic drugs can be used as adjuvants in cancer chemotherapy to act by multi-targeted therapeutic approach so as to reduce dose, side effects and resistance. Cytokines such as IL-8, TNF-α, VEGF are important components of tumor microenvironment and play major role in cancer invasion, angiogenesis and metastasis. Bax and Bcl-2 are proteins of apoptotic pathway that check for cell survival and senescence. Anti-proliferative, anti-angiogenic and pro-apoptotic activities of NS and THM, unequivocally demonstrates their potential as adjuvants for taxane therapy in ovarian cancer.
Combination of NS and THM with DTX and PTX stalls SKOV3 growth through IL-8, TNF-α, VEGF and Bax/Bcl-2 mediated pathways.
Citation Format: Rajani Mathur, Mukesh Tiwari. Antiproliferative, antiangiogenic and proapoptotic actions qualify Nigella sativa as taxane therapy adjuvant in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A53.