bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B2-45: Uncovering coordinated regulation of transcription factors by microRNAs using integrated network models
Authors: Gosline Sara JC , Gurtan Allan M. , JnBaptiste Courtney K. , Bosson Andrew , Milani Pamela , Dalin Simona , Matthews Bryan , Yap Yoon Sing , Sharp Phillip A. , Fraenkel Ernest 
Published: May 2016

Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play a significant role in development and cancer but induce only moderate repression of direct messenger RNA (mRNA) targets, suggesting that they coordinate with other modes of cellular regulation to affect cellular phenotype. In this work we exhaustively profile the transcriptional and post-transcriptional regulatory changes between an isogenic pair of murine fibroblast cell lines with and without Dicer, an enzyme required for miRNA processing. Through quantitative analysis of diverse high-throughput datasets collected from both cell lines, we were able to decouple transcriptional from post-transcriptional changes reflected in mRNA expression changes between cells with and without miRNAs.
We present three major findings. First, we find that direct miRNA-mRNA interactions have a limited impact on gene expression changes upon Dicer deletion when compared to changes at transcription. We then introduce an integrative graphical network approach to identify specific transcription factors that explain the observed changes in gene expression upon loss of Dicer. Validation of this computational model via transcription factor over-expression reveals a subset of the miRNA-mediated transcriptional program that is activated upon Dicer loss, confirming that transcriptional networks amplify the effects of miRNAs. Lastly, we use this network to examine coordination between transcriptional and post-transcriptional regulation. We identify numerous coherent and in-coherent feed-forward loops, network motifs that have been alluded to but only minimally studied in the context of microRNAs and transcription factors, and find that genes regulated within feed-forward loops by microRNAs and transcription factors exhibit distinct properties in development.
In summary, our work illustrates how transcriptional networks amplify the effects of microRNAs. We show coordinated regulation of transcription factors by microRNAs that suggests that most gene expression changes attributed to microRNAs in diseases such as cancer are due to changes in transcription rather than microRNA-mediated degradataion. As such, this work has the potential to reframe future studies of microRNAs in the context of cancer by shifting the focus to understanding the impact of microRNAs on transcription factors.
Citation Format: Sara JC Gosline, Allan M. Gurtan, Courtney K. JnBaptiste, Andrew Bosson, Pamela Milani, Simona Dalin, Bryan Matthews, Yoon Sing Yap, Phillip A. Sharp, Ernest Fraenkel. Uncovering coordinated regulation of transcription factors by microRNAs using integrated network models. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-45.
Abstract PR09: Extracellular stiffness cues drive spatial reorganization of the genome to globally constrain RNA abundance
Authors: Bainer Russell , Yui Yoshihiro , Mumenthaler Shannon , Mallick Parag , Liu Lin , Wu Hua-Jun , Podlaha Ondrej , Michor Franziska , Liphardt Jan , Licht Jonathan , Weaver Valerie 
Published: May 2016

Abstract
The stiffness of the extracellular matrix (ECM) drives mechanosignaling that regulates tissue development and malignancy. We previously showed that a stiff ECM disrupts tissue organization and enhances malignant progression by inducing cell invasion and migration. However, the specific transcriptional and molecular events in which mechanotransduction directs these phenotypes are not well understood. To clarify this process, we used a combination of genome-scale approaches to monitor changes in gene expression and protein abundance as a function of acinar morphogenesis and tissue homeostasis in three dimensional extracellular matrix hydrogels with tunable stiffness. Elevated ECM stiffness perturbed tissue homeostasis and reverted the transcriptional phenotype of differentiated mammary acini to resemble that observed in rapidly proliferating nonpolarized mammary cell aggregates. These findings suggest that tissue tension induces cellular changes that directly reflect higher-order tissue organizational states. We found that these changes involve the spatial rearrangement of peripheral chromatin, and that the expression levels of multiple histone deacetylases increase in organized tissues concurrently with elevated nuclear heterochromatin content, an effect that is abrogated in rigid ECM conditions. We support these observations by mapping mechanoresponsive peripheral heterochromatin elements via ChIPseq, enabling us to directly identify dynamic regions containing genes whose transcriptional activity is responsive to mechanical cues. Finally, using a combination of genomic, imaging, and molecular biology techniques we demonstrated that ECM compliance and tissue organization significantly influences global RNA abundance. Notably, this model presents formidable conceptual and practical challenges for the interpretation of genomic data. Collectively, this work indicates that tissue organization is critically dependent on the cellular mechanical environment, which qualitatively and quantitatively shapes the epigenetic and transcriptional landscape by mechanisms that have not yet been elucidated.
Note: This abstract was not presented at the conference.
Citation Format: Russell Bainer, Yoshihiro Yui, Shannon Mumenthaler, Parag Mallick, Lin Liu, Hua-Jun Wu, Ondrej Podlaha, Franziska Michor, Jan Liphardt, Jonathan Licht, Valerie Weaver. Extracellular stiffness cues drive spatial reorganization of the genome to globally constrain RNA abundance. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR09.
Abstract B42: A two-lncRNA signature in serous exosomes serves as a new biomarker for colorectal cancer diagnosis
Authors: Qi Peng , Dong Lei , Lin Wanrun , Zhou Xiaoyan , Du Xiang 
Published: May 2016

Abstract
Background: Many studies have shown that long non-coding RNAs (lncRNAs) participate in the initiation and development of colorectal cancer (CRC). We previously reported that lncRNAs can be detected and are stable in serum. Exosomes (EXOs) are small (30 to 100 nm) membrane-bound particles that are released from normal, diseased, and neoplastic cells and are present in blood and other bodily fluids. EXOs contain a variety of molecules including signal peptides, mRNA, microRNA, and lipids. However, it is unclear if lncRNAs in serous EXOs represent a novel marker to detect CRC.
Methods: Total RNA and serous EXO RNA were isolated from serum of 60 CRC patients, 60 age- and sex-matched healthy subjects. We measured 39 candidate cancer-associated lncRNAs by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in EXO RNA samples. The putative lncRNA markers identified in the training set (30 CRC patients and 30 healthy subjects) were verified in the test set (another 30 CRC patients and 30 healthy subjects). We further analyzed the putative lncRNA markers in serum total RNA samples.
Results: In the training set, 16 lncRNAs were detectable in serous EXOs, and the expression levels of 7 lncRNAs were significantly different between healthy samples and CRC samples (p&lt;0.05). Stepwise regression analysis showed that the combination of prostate cancer associated 3 (PCA3) and breast cancer anti-estrogen resistance 4 (BCAR4) provided the greatest predictive ability, with an AUC of 0.896 (95% CI: 0.794-0.921, p=0.029). Using the same serum samples, we compared the AUC values of these two lncRNAs in EXO with those in total RNA samples. The AUC values of our serous EXO two-lncRNA signature were markedly higher than those of serum signature (AUC=0.759, 95% CI: 0.696-0.853) for discriminating CRC patients from controls. The predictor was remarkably stable when applied to the test set comprising 30 CRC patients and 30 matched controls, with an AUC of 0.875. The AUC values of the serous EXO two-lncRNA signature for the test set were also markedly higher than those of serum signature (AUC=0.742 95% CI: 0.653-0.801) for discriminating CRC patients from controls. The results indicated that the two-lncRNA signature in serous EXO is an accurate biomarker for CRC diagnosis
Conclusions: The PCA3 and BCAR4 signature in serous EXOs may facilitate the detection of CRC and serve as the basis for further studies of the clinical value of circulating lncRNAs in maintaining surveillance and forecasting prognosis.
Citation Format: Peng Qi, Lei Dong, Wanrun Lin, Xiaoyan Zhou, Xiang Du. A two-lncRNA signature in serous exosomes serves as a new biomarker for colorectal cancer diagnosis. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B42.
Abstract P2-02-03: HER2 expression on circulating tumor cells before adjuvant chemotherapy and during follow-up in patients with HER2-negative early breast cancer
Authors: Markomanolaki H , Mavroudis D , Kallergi G , Vetsika E-K , Stratigos M , Makrigiannaki K , Georgoulias V , Agelaki S 
Published: May 2016

Abstract
Background: Detection of circulating tumor cells (CTCs) before adjuvant chemotherapy as well as during follow-up is related to poor prognosis in early breast cancer. The presence of HER2-positive CTCs has been also associated with significantly decreased disease-free and overall survival. We hereby assessed the HER2 status of CTCs in HER2-negative patients with early breast cancer, before the initiation of adjuvant chemotherapy and during follow-up. Methods: Double staining immunofluorescent experiments using pancytokeratin (A45-B/B3) and HER2 antibodies were performed in peripheral blood mononuclear cells (PBMCs) of patients. Patients were evaluated before adjuvant therapy (n=103) and during follow-up (n=290) at intervals ranging from 6 months to 20 years post-chemotherapy. Results: CTCs were detected in 28 (27.2%) out of 103 patients pre-chemotherapy and in 94 (32.4%) out of 290 during follow-up. The mean CTC count detected at ≤2 years of follow-up was not significantly different compared to baseline [3.4 CTCs (range 1-13) vs 2.9 (range 1-12), respectively]. However, this value showed a significant decrease from 2-5 to ≥10 years of follow-up (4.2, range 1-11 vs. 1.8, range 1-4). Among CTC-positive patients, CTCs expressing HER2 were detected in 21 (75%) and in 73 (77.7%) patients pre-chemotherapy and during follow-up, respectively. The mean proportion of HER2-positive CTCs per patient was 73.5% pre-chemotherapy and 67% at follow-up. This proportion showed a significant increase at follow-up time points ≤2, 2-5 and 5-10 years [52% (p=0.0027), 65.6% (p=0.0476) and 69% (p=0.0440), respectively] compared to ≥10 years (89.2%). Conclusions: These data demonstrate that CTCs persist during follow-up in a significant percentage of early breast cancer patients. Similarly, HER2 positive CTCs are detected in a significant proportion of patients both at baseline and during follow-up. Mean CTC count appears to decrease after 10 years, whereas the population of HER2 positive CTCs seems to increase during follow-up. These results suggest that targeting HER2-positive CTCs may have implications for the prevention of late relapses.
Citation Format: Markomanolaki H, Mavroudis D, Kallergi G, Vetsika E-K, Stratigos M, Makrigiannaki K, Georgoulias V, Agelaki S. HER2 expression on circulating tumor cells before adjuvant chemotherapy and during follow-up in patients with HER2-negative early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-03.
Abstract IA13: Inhibiting the Wnt pathway with selective anti-Frizzled synthetic antibodies
Authors: Steinhart Zachary , Hart Traver , Sidhu Sachdev , Moffat Jason , Angers Stephane 
Published: May 2016

Abstract
Secreted Wnt glycoproteins regulate intracellular signaling pathways important for embryonic development and adult tissue homeostasis. Misregulation of Wnt signalling is frequent in human cancers. Wnt ligands are recognized at the surface of cells by various receptor complexes that are differentially expressed and determine context-dependent cellular responses. In humans, 16 Wnt ligands interact directly with 10 Frizzled seven transmembrane proteins through their extracellular cysteine rich domain (CRD). Wnts also interact with various co-receptors, such as LRP5/6, ROR1/2, RYK, PTK7, which engage different downstream signaling pathways. While genetic analysis of mouse knockouts has revealed specific roles for different Wnt receptors and co-receptors during embryonic development, relatively little is known about their respective functions during adult tissue homeostasis or in the initiation and progression of human diseases such as cancer. There is a paucity of reagents allowing the selective and temporal pharmacological inhibition of Wnt receptors. We are employing phage-display technology to identify high affinity synthetic blocking monoclonal antibodies (mAbs) against all human Wnt receptors. To date we have isolated a collection of anti-receptor antibodies exhibiting unique selectivity and functionality profiles. Our lead anti-Frizzled mAbs targeting a subset of Frizzled proteins inhibit Wnt-promoted activation of the TopFlash reporter with low nanomolar potency. These mAbs also exhibit dose dependent anti-proliferative efficacies against various pancreatic cancer cell lines grown in vitro and as xenografts in mice.
These reagents will be useful to probe the function of specific Wnt receptors in tissue homeostasis and human diseases and will lead to novel therapeutic agents for their treatment.
Our lab is also employing whole genome CRISPR screening approach to identify genotype specific vulnerabilities in cancer cells. These efforts have identified specific Frizzled important for cancer cells proliferation and is guiding our antibody development program.
Citation Format: Zachary Steinhart, Traver Hart, Sachdev Sidhu, Jason Moffat, Stephane Angers. Inhibiting the Wnt pathway with selective anti-Frizzled synthetic antibodies. [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 IA13.
Abstract A09: The role of asparagine in glutamine-independent proliferation of breast cancer cells
Authors: Pavlova Natalya N. , Thompson Craig B. 
Published: May 2016

Abstract
The majority of proliferating cells utilize the carbon backbone of glutamine as a major anaplerotic input into the TCA cycle. In addition, glutamine serves as a donor of reduced nitrogen for the biosynthesis of purine and pyrimidine nucleotides, as well as for a number of non-essential amino acids. Thus, cells rely on external sources of glutamine for biomass accumulation and growth. However, recent data indicate that some cancer cell types – luminal breast cancer lines in particular – are able to proliferate in the absence of exogenous glutamine. Furthermore, luminal breast cancer lines display increased expression of GLUL (glutamine synthetase) and reduced expression of GLS1 (glutaminase), when compared to basal subtype.
We sought to identify key metabolic determinants of glutamine-independent proliferation. As our preliminary data indicate, the presence of amino acid asparagine is required for the proliferation of luminal breast cancer cells as well as normal breast epithelial cells in the setting of glutamine deprivation. Both asparagine and glutamine contain amide groups in their respective side chains and are thus structurally similar to each other. However, most normal mammalian tissues – with the exception of the liver and the kidney – are unable to catabolize asparagine, making it essentially metabolically inert for the majority of cell types. Our group has previously shown that asparagine suppresses cell death in cells that depend on glutamine for survival. In this study, we attempt to elucidate the mechanism by which asparagine facilitates the biomass accumulation and proliferation of glutamine-independent cell types. First, we investigate whether luminal breast cancer cells may possess an ability to catabolize asparagine in a manner similar to glutaminolysis and thus use it as an alternative source of reduced nitrogen and carbon in a setting of glutamine deprivation. Second, we explore a potential regulatory metabolic function of asparagine, whereby it may regulate cellular glutamine synthesis and thus enable proliferation in conditions of glutamine deprivation.
Citation Format: Natalya N. Pavlova, Craig B. Thompson. The role of asparagine in glutamine-independent proliferation of breast cancer cells. [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 A09.
Abstract A20: Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and enables glucose-independent tumor cell growth
Authors: Vincent Emma E. , Sergushichev Alexey , Griss Takla , Artyomov Maxime N. , Jones Russell G. 
Published: May 2016

Abstract
Cancer cells must adapt metabolically to survive and proliferate when nutrients are limiting. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell growth. We found that glucose deprivation stimulated the re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote cell proliferation under low glucose. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine, which was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. Mitochondrial PEP-carboxykinase (PCK2) was required for this glutamine-dependent metabolic reprogramming. PCK2 expression was dependent on the hypoxia-inducible factors (HIFs), and required to maintain tumor cell proliferation under limiting glucose availability. Elevated PCK2 expression is observed in several human tumor types, and enriched in tumor tissue from non-small cell lung cancer (NSCLC) patients. Our results define a novel role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.
Citation Format: Emma E. Vincent, Alexey Sergushichev, Takla Griss, Maxime N. Artyomov, Russell G. Jones. Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and enables glucose-independent tumor cell 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 A20.
Abstract B27: Kras alters expression of asparagine synthetase (Asns) in non-small cell lung cancer (NSCLC) and protects tumors during nutrient stress
Authors: Gwinn Dana M. , Sweet-Cordero Alejandro 
Published: May 2016

Abstract
Kras is a small GTPase that functions in the transmission of extracellular mitogenic stimuli, and is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC). Previously, Kras has been demonstrated to play a role in tumor metabolism in certain cell types and cancers, but this has yet to be analyzed in the context of NSCLC. We have analyzed how Kras changes metabolic gene expression by expressing a doxycycline-inducible hairpin against Kras in 4 NSCLC cell lines. One of the most regulated metabolism genes is asparagine synthetase (Asns), which transfers the γ-amino group of glutamine to aspartate, yielding glutamate and asparagine. We find elevated levels of Asns in Kras mutant tumors, and that expression of Asns correlates with poor patient outcome. Knockdown of Asns in the absence of exogenous asparagine in the media results in inhibition of cell growth and induction of apoptosis that is rescued by addition of asparagine. Additionally, under conditions of low glutamine levels, knockdown of Asns sensitizes cells to apoptosis, and overexpression of Asns is protective under these conditions. We also find a role for the glutaminase-activity of Asns in glutamine-mediated anapleurosis of the TCA cycle. These observations suggest Asns may be an interesting therapeutic target for NSCLC tumors with mutations in Kras.
Citation Format: Dana M. Gwinn, Alejandro Sweet-Cordero. Kras alters expression of asparagine synthetase (Asns) in non-small cell lung cancer (NSCLC) and protects tumors during nutrient stress. [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 B27.
Abstract B32: FOXOs support the metabolic requirements of normal and tumor cells by regulating IDH1 expression
Authors: Charitou Paraskevi , Rodriguez-Colman Maria , Gerrits Johan , Verhoeven-Duif Nanda , Burgering Boudewijn 
Published: May 2016

Abstract
FOXO transcription factors are considered bona fide tumor suppressors, however recent studies showed FOXOs are also required for tumor survival. Here we identify FOXOs as transcriptional regulators of IDH1. FOXOs regulate IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. In cancer cells carrying mutant IDH1, FOXOs likewise regulate mutant IDH1 expression and maintain the levels of the oncometabolite 2-hydroxyglutarate, which stimulates cancer cell proliferation likely by repressing differentiation. Combined, our data provide a new paradigm for the paradoxical role of FOXOs in both tumor suppression and promotion. Furthermore these data suggest a role for FOXOs in maintaining the de-differentiated state by regulating α-ketoglutarate and/or 2-hydroxyglutarate levels. Indeed, in models of differentiation (e.g. 3T3-L1 differentiation towards adipocytes) loss of FOXO, as well as loss of IDH1 expression repress differentiation and we are currently further exploring the molecular underpinnings.
Note: This abstract was not presented at the conference.
Citation Format: Paraskevi Charitou, Maria Rodriguez-Colman, Johan Gerrits, Nanda Verhoeven-Duif, Boudewijn Burgering. FOXOs support the metabolic requirements of normal and tumor cells by regulating IDH1 expression. [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 B32.
Abstract B44: Functional identification of a mitochondrial glutamine carrier using isotope tracers
Authors: Metallo Christian 
Published: May 2016

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR07) of the Conference Proceedings.
Citation Format: Christian Metallo. Functional identification of a mitochondrial glutamine carrier using isotope tracers. [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 B44.