bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A23: The crosstalk between developmental endothelial locus 1 (DEL-1) and cancer stem cells in murine melanoma: A potential modality of local control
Authors: Walker James , kocherla marsha , christianson Blake , qin Xu , yu Jack C. , baban Babak 
Published: May 2016

Abstract
Introduction: Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Del-1 has an endothelial cell–restricted pattern, particularly in the embryo. However, our data now for the first time provide evidence that melanoma cells express Del-1. The relatively newly described cancer stem cells (CSCs) are tumor-initiating cells (TICs) that often survive therapy and give rise to second-line tumors by self-renewal and differentiation into multiple cell types. CSCs are proposed to persist in tumors as a distinct population and to cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially those with metastatic disease. Methods: C57/BL6 mice were injected with B16F10 murine melanoma cell line (1 x 106 cells/mouse, subcutaneous). Tumor growth monitored. Controls (Group 2) received vehicle only (PBS). Once the first tumor reached 12mm in size, the mice were sacrificed and tumor cells subjected to flow-cytometry, and statistical analysis, and p-values &lt;0.05 considered significant. our novel findings suggest a regulatory role for Del-1 in cancer. Alteration of inflammatory indices, apoptosis, and necroptosis with ultimate affects on tumor size and growth were all may be potentially regulated partially by a Del-1 dependent mechanism. Results: Our data showed for the first time that DEL-1 was expressed by CSCs as well as typic non stem cells tumor cells in a murine melanoma model. These DEL-1-expressing CSCs may be palying a role in tumor angiogenesis. Further, DEL-1 is capable of suppressing T lymphocyte infiltration into the tumor microenvironment.
our novel findings suggest a regulatory role for Del-1 in cancer. Alteration of inflammatory indices, apoptosis, and necroptosis with ultimate affects on tumor size and growth (by affecting Cancer Stem Cells) were all may be potentially regulated partially by a Del-1 dependent mechanism. Conclusion: Our data propose a novel hypothesis that development of tumor and CSCs activity may be affected by angiogenic and regulatory nature of Del-1. Furthermore, our results suggest a therapeutic role for Del-1 as a novel modality in cancer treatment.
Citation Format: James Walker, marsha kocherla, Blake christianson, Xu qin, Jack C. yu, Babak baban. The crosstalk between developmental endothelial locus 1 (DEL-1) and cancer stem cells in murine melanoma: A potential modality of local control. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A23.
Abstract A26: Cofactor of BRCA1 as a modulator of hepatocellular carcinoma growth and migration
Authors: Zeneini Eman El , Amleh Asma 
Published: May 2016

Abstract
COBRA1 is one of the four subunits that make up the Negative Elongation Factor Complex (NELF) which is involved in the stalling of RNA polymerase II early during transcription elongation. As such, COBRA1 is able to regulate a substantial number of genes involved in a number of pathways, including cell cycle control, metabolism, cell proliferation and DNA repair. Even though it has been extensively studied over the years, the majority of these studies have mostly reported physiological roles. In the field of cancer, COBRA1 remains largely unexplored. The aim of our study was to investigate the functional role of COBRA1 in the tumorigenesis of hepatocellular carcinoma (HCC). We investigated the gene expression pattern of COBRA1 in HCC tumors using the publicly available Oncomine Cancer Microarray Database. Results from three different microarray datasets reveal the frequent overexpression of COBRA1 in HCC tumors versus their normal counterparts. To elucidate the biological significance for this overexpression in HCC, RNA interference was used to silence the expression of COBRA1 in the well differentiated cell line, HepG2. The silencing efficiency was confirmed by both RT-PCR and Western blot analysis. Interestingly, knockdown of COBRA1 resulted in a significant decrease in cell proliferation, accompanied by a concomitant decrease in the expression of the proliferation marker, Ki-67. A scratch wound healing assay revealed a significant decrease in the migratory potential of the HepG2 cells in culture as well upon COBRA1 knockdown. The silencing of COBRA1 was associated with a significant decrease in the expression of survivin, suggesting that survivin might be one of the mechanisms by which COBRA1 mediates its role in the tumorigenicity of HCC. Collectively, data findings presented here highlight an oncogenic role for COBRA1 in hepatocellular carcinoma. To the best of our knowledge, our study provides evidence for the first time to support a positive role for COBRA1 in the growth and migration of HCC.
Note: This abstract was not presented at the conference.
Citation Format: Eman El Zeneini, Asma Amleh. Cofactor of BRCA1 as a modulator of hepatocellular carcinoma growth and migration. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A26.
Abstract A28: New data supporting the possible evolutionary role of tumors: Evolutionary novel genes expressed in fish tumors determine progressive evolutionary characters in humans
Authors: Kozlov Andrei , Matyunina Ekaterina , Emelyanov Alexander 
Published: May 2016

Abstract
The origin of evolutionary novel genes in DNA of germ cells is connected with the origin and evolution of the novel organismal functions and the increase in morphological complexity of multicellular organisms. Novel gene acquire new or altered functions. Here we describe that evolutionary novel genes, expressed predominantly in transgenic fish tumors after their induced regression, determine progressive evolutionary characters and are conserved in humans. We used a sample of genes, which were activated in inducible krasV12 transgenic zebrafish tumors according to the results of RNASeq data. Genes from our sample were expressed after HCC regression upon kras inactivation. The search of orthologs by different tools, such as blastx and psiblast, with e-value cut off not less than 10-3 and query coverage more than 50%, discovered that considerable proportion of tumor-specifically expressed genes are evolutionary novel, i.e. their orthologs are not found in lamprey. 226 of these novel genes have orthologs in humans. Gene ontology (GO) data were used to analyze their functions. According to the results of GO some of the genes have functions not characteristic to fish. For example, genes ccdc40, lmx1ba, lepa, tgfbr2 and irs1 acquired functions in lung, embryonic utera, mammalian placenta and mammary gland, i.e. organs originated in taxa higher than fish. Among known functions of the human orthologues of evolutionary novel genes of zebrafish (vs. lamprey) there are some important morphogenetic functions. A large proportion of genes from our sample are connected with retina type eye, heart, lung and brain development.
Note: This abstract was not presented at the conference.
Citation Format: Andrei Kozlov, Ekaterina Matyunina, Alexander Emelyanov. New data supporting the possible evolutionary role of tumors: Evolutionary novel genes expressed in fish tumors determine progressive evolutionary characters in humans. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A28.
Abstract B07: Tumor promoting activity of SLC13A3 in metastatic prostate cells
Authors: Zhunussova Aigul , Irgebayeva Zhanar , Sen Bhaswati , Friedman Leah , Ossikbayeva Saniya , Tuleukhanov Sultan , Brooks Ari , Sensenig Richard , Orynbayeva Zulfiya 
Published: May 2016

Abstract
Solute carriers are membrane proteins that play an important role in cancer homeostasis by supplying cancer cells with essential building blocks and signaling molecules. Different types of membrane transporters were shown to be overexpressed in tumors in support of tumor growth and survival. Due to high affinity interaction with anticancer drugs they can also significantly contribute to the rapid chemoresistance. There is a limited number of studies on the role of solute carriers in reprogramming of cancer metabolism and signaling, especially in metastatic prostate cancer.
Our study enabled us to establish the identity of the prostate cancer solute carrier that supports uptake of succinate and possibly similar energy rich metabolites from tumor microenvironment to promote an elevated energy metabolism of cancer cells. We demonstrated that prostate metastatic DU145 cells acquire Na+-dependent dycarboxylic acid carrier SLC13A3 but normal prostate PrEC cells do not express this protein. An important finding was that only at acidic pH 6.8 prostate cancer cells are capable of consuming exogenous succinate, while physiological pH 7.4 was not favorable for this process. Importantly, succinate transported by SLC13A3 not only accelerates the oxidative phosphorylation of prostate cancer mitochondria but it is also known to stabilize onco-factor HIF-1α. The HIF-involved signaling pathways have been linked to prostate tumorigenesis and chemoresistance and therefore, targeting these pathways by inhibiting cancer specific SLC13A3 has great potential for clinical benefit. In addition, the mechanism of succinate influx via SLC13A3 transporter in metastatic prostate cancer cells could also yield a novel metabolic onco-marker and has the potential to be used for imaging-based diagnostics to detect non-glycolytic tumors.
Citation Format: Aigul Zhunussova, Zhanar Irgebayeva, Bhaswati Sen, Leah Friedman, Saniya Ossikbayeva, Sultan Tuleukhanov, Ari Brooks, Richard Sensenig, Zulfiya Orynbayeva. Tumor promoting activity of SLC13A3 in metastatic prostate cells. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B07.
Abstract B09: Differential effect of microenvironment on tumor phenotype using an immature T cell lymphoma mouse model
Authors: Lucas Philip J. , Gress Ronald E. 
Published: May 2016

Abstract
Human T cell lymphomas of an immature phenotype with mediastinal origin are classified as T cell lymphoblastic lymphomas (T-LBL) and comprise 85-90% of all lymphoblastic lymphomas. Treatment of T-LBL can be challenging because of the metastasizing nature of the disease, which commonly localizes to the bone marrow and can be found in other organs such as liver and spleen. We have developed a mouse T-LBL model by establishing a cell line from a spontaneous mediastinal tumor found in a T cell receptor (TCR) transgenic mouse strain. The resulting T-LBL like cell line, JMR4, has a known TCR (2C), known alloreactivity (H-2Ld), and known stimulating self-peptide (SIYR). JMR4 has an immature T cell phenotype, which includes a mixture of CD4+/CD8+, CD4lo/CD8+, CD4+/CD8lo and CD4+ cells. Other T cell markers, such as CD5, CD24 and CD69 are expressed at various levels depending on the phenotypic subset. The 2C TCR, which can be detected using the 1B2 idiotypic mAb, has been shown to be functional using flow cytometric analysis following TCR stimulation using peptide loaded thymic stromal feeder cells. In addition, JMR4 can be phenotypically altered (CD4/CD8/CD5/CD69 expression levels) differentially in vitro using the bone marrow stromal cell line OP9 and OP9DL, suggesting that it has pluripotency. Finally, when JMR4 is injected into sub-lethally irradiated mice, it develops into a multi-organ lymphoma. Interestingly, the phenotype of the JMR4 cells, based on CD4 and CD8 expression levels, is differentially regulated depending on organ type and MHC of the host, making JMR4 an ideal model to study the complex interactions of a tumor with its microenvironment. Understanding the mechanisms involved in tumor microenvironment (TME) induced changes to tumor cells should be important in understanding metastatic tumor progression and in designing new treatment regimens.
Citation Format: Philip J. Lucas, Ronald E. Gress. Differential effect of microenvironment on tumor phenotype using an immature T cell lymphoma mouse model. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B09.
Abstract B10: Cyclin D1 restrains oncogene-induced autophagy via phosphorylation of LKB1
Authors: Casimiro Mathew , Sante Gabriele Di , Loro Emanuele , Pestell Timothy , Bisetto Sara , Velasco-Velázquez Marco , Jiao Xuanmao , Li Zhiping , Wang Chenguang , Ly Daniel , Zheng Bin , Che-Hung Shen , Ertel Adam , Pestell Richard G. 
Published: May 2016

Abstract
Cyclin D1 is an important molecular driver of many human cancers. The cyclin D1 gene is amplified or overexpressed in up to half of human breast cancers and mammary-targeted overexpression of cyclin D1 is sufficient to induce mammary tumorigenesis in mice. Cyclin D1 encodes the regulatory subunit of the cyclin-dependent kinase (CDK) holoenzyme that phosphorylates several substrates including the retinoblastoma protein (pRb) to advance the G1S cell cycle checkpoint and promote DNA synthesis. Recent studies have implicated cell cycle regulators that govern G1S transition, in regulating cellular metabolism. Cyclin D1 phosphorylates and inactivates a nuclear encoded protein essential for mitochondrial biogenesis, Nrf1. In this manner cyclin D1 coordinates both nuclear and mitochondrial functions. Consistent with cyclin D1-dependent inhibition of mitochondrial biogenesis, pRB promotes and E2F-1 inhibits mitochondrial biogenesis. In addition to inhibiting mitochondrial biogenesis, cyclin D1 inhibits mitochondrial membrane potential, which may be in part due to binding VDAC.
Autophagy is a catabolic pathway activated in response to cellular stress such as oxidative or nutritional stress. It mitigates cellular damage via removal of insoluble and damaged proteins, lipids and organelles. Autophagy is enhanced by the phosphorylated and activated form of 5’-AMP-activated protein kinase (AMPK). We initiated the following study to directly test the effect of cyclin D1 has on cellular metabolism and autophagy. Herein, endogenous cyclin D1 restrained autophagy in breast cancer cells in tissue culture and in the mammary gland of mice. Using mammary epithelial-targeted deletion of cyclin D1 we show cyclin D1 restrains autophagy by reducing AMPK activation. Cyclin D1 may serve to couple cellular proliferation to cellular energy homeostasis.
Citation Format: Mathew Casimiro, Gabriele Di Sante, Emanuele Loro, Timothy Pestell, Sara Bisetto, Marco Velasco-Velázquez, Xuanmao Jiao, Zhiping Li, Chenguang Wang, Daniel Ly, Bin Zheng, Shen Che-Hung, Adam Ertel, Richard G. Pestell. Cyclin D1 restrains oncogene-induced autophagy via phosphorylation of LKB1. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B10.
Abstract B20: Single-cell profiling of EGFR-regulated protein changes involved in cell cycle, cell proliferation and apoptosis
Authors: Holcomb Ilona , Dakshinamoorthy Gajalakshmi , Liu Benjamin , Unger Marc , Ramakrishnan Ramesh , Gong Haibiao 
Published: May 2016

Abstract
Single-cell molecular analysis has become increasingly important in biomedical research, especially in the field of cancer research, where cell heterogeneity is a characteristic feature. We developed a multiplexed single-cell protein detection assay for the C1™ system that can isolate and process 96 individual cells in parallel. The assay uses oligonucleotide-conjugated antibody binders and monitors the specific oligonucleotide levels instead of protein levels. The resulting DNA amplicon is detected by qPCR on the Biomark™ HD system. Data are analyzed using Singular™ Analysis Toolset. A total of 50 antibody binders were developed for this assay to target proteins related to apoptosis, cell cycle, cell proliferation, tumor suppressors, biomarkers, stem cells, growth factors and proteins associated with specific cancers, such as breast and prostate cancers. The assay can be performed in a 48-plex format which yields over 4,600 data points in two days. Assay sensitivity and specificity were assessed using recombinant proteins and various cell lysates. To demonstrate the usefulness of this assay, a panel of antibody binders was selected to profile the changes of proteins involved in cell cycle, cell proliferation and apoptosis in single cells. We treated cells that overexpress epidermal growth factor receptor (EGFR) with either the EGF ligand or the gefitinib receptor inhibitor and analyzed the changes in protein levels. Cells without EGFR expression were used as the control. EGFR is a member of ErbB family of Type I tyrosine kinases. EGFR overexpression and its mutations are involved in a variety of cancers. While much effort has been made to investigate the consequences of EGFR activation or inhibition, hardly any information is available regarding how EGFR regulation changes protein expression in single cells. Single-cell analysis—determining protein changes and analyzing the correlation between different proteins at the single-cell level—yields valuable information that is not achievable using bulk-cell analysis.
Citation Format: Ilona Holcomb, Gajalakshmi Dakshinamoorthy, Benjamin Liu, Marc Unger, Ramesh Ramakrishnan, Haibiao Gong. Single-cell profiling of EGFR-regulated protein changes involved in cell cycle, cell proliferation and apoptosis. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B20.
Abstract B22: Screening and validation of combination therapy in T cell leukemia
Authors: Mues Marsilius , Lindenbergh Marthe F. , McManus Michael T. , Roose Jeroen P. 
Published: May 2016

Abstract
Oncogenic Ras mutations occur in more than 30% of metastatic cancers. There are no effective inhibitors to block oncogenic K- or N-RAS, however, blockade of Ras’ downstream RAF-MEK-ERK and PI3K-Akt-mTOR-S6 signaling cascades is currently being explored as therapy in clinical trials through the use of potent kinase inhibitors. Nonetheless, many cancers have a complex make-up of cooperating oncogenic lesions and it is therefore questionable if inhibition of single molecules in pathways will provide sufficient, long-term efficacy. To explore effective combination therapies to treat Ras-driven cancers we chose synthetic lethal screens (SLS), focusing on PI3K due to its frequent involvement in oncogenic signaling. We performed a set of SLS on T cell leukemia (T-ALL) cell lines combining specific PI3K inhibitors with high coverage shRNA libraries, initially aiming at kinases. We employed the UCSF EXPANDed RNAi library resource, which dramatically improves RNAi screening compared to commercial resources. This ultra-complex shRNA library targets each gene with &gt;25 independent shRNAs, thus drastically minimizing experimental noise and allowing us to overcome both the common problems of high false-negative rates and high false-positive rates. Using deep sequencing of shRNAs recovered from our screening samples, we identified shRNAs that synergize with inhibitors in these drop-out SLS conditions and which represent key molecules for the survival of T-ALL lines. In addition, we also identified enriched shRNAs that confer inhibitor resistance or enhanced proliferation. To verify our screening results we used combinations of chemical inhibitors, targeting PI3K and molecules identified by our screens. To date, all inhibitor combinations tested caused strong synthetic lethality in T-ALL cells, confirming the robustness of the ultra-complex shRNA libraries used for SLS. The most promising results will be further verified in vivo, and we will expand our efforts to different leukemia and also solid cancer lines. Altogether, our high-troughput platform is a promising approach to identify effective partners for already established inhibitors, leading to novel combination therapies for the treatment of cancer.
Citation Format: Marsilius Mues, Marthe F. Lindenbergh, Michael T. McManus, Jeroen P. Roose. Screening and validation of combination therapy in T cell leukemia. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B22.
Abstract B23: Chemoproteomic profiling of native kinases during the treatment of cells with kinase inhibitors
Authors: Nomanbhoy Tyzoon K. , Brown Heidi E. , Wu Jiangyue , Vogeti Subha , Aban Arwin , Grant Wendy , Senait Alemayehu , Wu Shuzhen , Dias Christa , Sharma Geeta 
Published: May 2016

Abstract
Kinases are an important class of targets for a number of therapeutic indications, and currently, kinase inhibitors constitute a significant fraction of recently approved drugs, particularly for cancer. Using a probe-based chemoproteomics platform, we have demonstrated the utility of the platform to monitor the interactions between inhibitors and native kinases. Herein, we profile kinase inhibitors in cell lines either sensitive or resistant to the compound for various periods of time. We observe that at early time points, inhibitor profiles for a compound are qualitatively similar in both the sensitive and resistant cells, suggesting the compound is capable of engaging its direct targets in both cell types. In contrast, at later time points, additional kinases are observed affected by compound treatment. We infer that these kinases do not directly bind the compound but rather reflect secondary effects that result from the engagement of the primary targets (pathway effects). Significantly, the pathway effects are only observed in the sensitive cells and not the resistant cells. Kinases affected through these pathway effects include kinases known to be critical for cell cycle progression including CDK1, Aurora A and B, PLK1, and MASTL. Finally, we demonstrate that during the treatment of tumor-bearing mice with an inhibitor, in addition to inhibition of the direct targets, pathway effects are observed recapitulating the results from the cell-based studies.
Citation Format: Tyzoon K. Nomanbhoy, Heidi E. Brown, Jiangyue Wu, Subha Vogeti, Arwin Aban, Wendy Grant, Alemayehu Senait, Shuzhen Wu, Christa Dias, Geeta Sharma. Chemoproteomic profiling of native kinases during the treatment of cells with kinase inhibitors. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B23.