bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B45: A cell-based screening to identify nucleolar disruptors in cancer cells
Authors: Morgado-Palacin Lucia , Llanos Susana , Blanco-Aparicio Carmen , Megias Diego , Pastor Joaquin , Serrano Manuel 
Published: August 2014

Abstract
Cancer cells require highly elevated levels of ribosome biogenesis to meet the demand for increased protein synthesis. Ribosome biogenesis, one of the most energy demanding processes, takes place in nucleoli. Notably, changes in number, size and morphology of nucleoli have been long recognized as a reliable feature of cancer cells. Interestingly, the nucleolus is well known to be a hub in the stress response. Approximately 70% of the ~4500 nucleolus-associated proteins are involved in functions other than ribosome biogenesis, including cell cycle control, apoptosis or DNA repair. This places the nucleolus as an important integrator between ribosome synthesis, cell cycle progression and stress signaling. A large variety of cellular insults trigger alterations in the dynamics of nucleolar proteins and/or ribosomal RNA. Stabilization of the tumor suppressor p53 has been observed as a result of the relocalization of certain ribosomal proteins in the nucleoplasm, notably L5 and L11, where they can bind and inhibit MDM2.
The aim of this work is to identify new potential anti-tumoral drugs by means of disrupting the nucleolar integrity. By using a high content cell-based screening in which nucleolar morphology is monitored by GFP-L37, we have identified several compounds that cause nucleolar disruption thereby leading cancer cells to proliferative arrest or apoptosis. Interestingly, one of our best hits is compound 2,4,7,9-tetramethylbenzo[b][1,8]naphthyridin-5-amine (TMBNA). This compound has been previously reported by other investigators to intercalate DNA and to activate p53, although the underlying molecular pathway is unknown. Our data indicates that TMBNA activates p53 through nucleolar disruption and binding of the ribosomal protein L11 to MDM2, ultimately resulting in cell cycle arrest and apoptosis. These results highlight the relevance of the nucleolus as a main target of cancer drugs.
Citation Format: Lucia Morgado-Palacin, Susana Llanos, Carmen Blanco-Aparicio, Diego Megias, Joaquin Pastor, Manuel Serrano. A cell-based screening to identify nucleolar disruptors in cancer cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B45.
Abstract B54: Squamous cell carcinoma antigen 1 (SCCA1) promotes mammary tumorigenesis through the induction of misfolded protein stress
Authors: Sheshadri Namratha , Ullman Erica , Catanzaro Joseph , Pan Ji-An , Chen Emily , Zong Wei-Xing 
Published: August 2014

Abstract
SCCA1, a member of the serine/cysteine protease inhibitor family, is upregulated in several cancers such as the cervix, lung, head and neck, liver, skin, and breast, and has been used as a diagnostic/prognostic marker. However, the biological function of SCCA1 in tumorigenesis remains largely unclear. Here we show that ectopic expression of SCCA1 in the non-tumorigenic mammary epithelial cell line MCF10A leads to spindle shaped cell morphology, increased cell migration, resistance to anoikis, foci formation in soft agar, as well as orthotopic tumor formation in immune-compromised mice. Gene expression analysis revealed that SCCA1 induces changes that are associated with epithelial-mesenchymal transition (EMT). Mechanistically, SCCA1 interferes with cellular protein homeostasis leading to a heightened unfolded protein response including the nuclear translocation of the transcriptionally active form of ATF6α. This increased ATF6α signaling results in NF-κB activation and increased pro-inflammatory response including an IL-6 autocrine signaling loop that drives EMT and transformation. These findings indicate a previously unknown role of SCCA1 in promoting tumorigenesis by inducing misfolded protein stress, NF-κB activation, and pro-tumorigenic cytokine signaling.
Citation Format: Namratha Sheshadri, Erica Ullman, Joseph Catanzaro, Ji-An Pan, Emily Chen, Wei-Xing Zong. Squamous cell carcinoma antigen 1 (SCCA1) promotes mammary tumorigenesis through the induction of misfolded protein stress. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B54.
Abstract B60: Interleukin-1 expression and inflammasome activation in human malignant glioma
Authors: Tarassishin Leonid , Lim Jihyeon , Lee Sunhee C. 
Published: August 2014

Abstract
Introduction: Interleukin 1 (IL-1) is a major proinflammatory cytokine produced by myeloid cells and is implicated in neurodegeneration. In human brain, IL-1 is expressed by microglia and contributes to neuroinflammation and neuronal toxicity. IL-1 is also the major activator of human astrocyte and glioma cells. In this study, we investigated the mechanism of IL-1 α and IL-1β expression and activation in human glioma cells.
Methods: Human glioblastoma cell lines (U87, U251, and SN19) as well as patient-derived glioma cell lines were stimulated with cytokines (IL-1/IFNγ) or TLR ligands (LPS or poly IC) and the expression of IL-1α and IL-1β was studied by real-time PCR, western blot analysis, and ELISA. The glioma secretome was investigated using quantitative mass spectrometry.
Results: We found that while primary human astrocytes show IL-1 translational block (no protein made despite high level of mRNA), but GBM cells responded strongly to IL-1 itself to produce large amounts of IL-1α and IL-1β mRNA and proteins. Furthermore, GBM cells processed pro-IL-1β (31kDa) to mature IL-1β (17kDa) by activating the NALP3 inflammasome. Both ATP and nigericin induced IL-1β processing by upregulating NALP3. Proteomics analysis of IL-1 stimulated GBM cell secretome revealed several highly upregulated proteins (IL-8, MCP-1, tenascin-C, pentraxin 3, galectin 1, and MMP2), all of which are implicated in glioma progression. Furthermore, many extracellular matrix proteins (ECM) and ECM-related proteins were downregulated by IL-1 in the glioma secretome.
Discussion: We propose that the ability of malignant glioma cells to produce IL-1 protein can set off chronic smoldering inflammation and induce epithelial-mesenchymal transition (EMT) resulting in increased migratory capacity, a unique gene signature, and increased immune signaling (NF-κB, pStat3). There is potential for IL-1 to be a biomarker/surrogate marker for a subset of GBM and that IL-1 blockade could benefit GBM patients.
Citation Format: Leonid Tarassishin, Jihyeon Lim, Sunhee C. Lee. Interleukin-1 expression and inflammasome activation in human malignant glioma. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B60.
Abstract B67: Elucidating the mechanism of targeting WNT ligands to exosomes
Authors: Zhang Ying Yi , Underhill Ainsley , Zhang Liang , Wrana Jeffrey 
Published: August 2014

Abstract
It has been demonstrated that secreted vesicles called exosomes derived from stromal fibroblasts pick up Wnt ligands from breast cancer cells and facilitate cell migration and metastasis in vivo. However, how Wnt ligands are loaded onto exosomes remains unclear. Interestingly, Wnt ligands are posttranslationally modified by acylation and thus tether tightly to the cell membrane. I will present my work on defining the molecular mechanisms through which Wnt is targeted to exosomes. In particular, I am studying the molecular determinants in Wnt ligands, including the palmitoylation and glycosylation sites that regulate Wnt sorting to exosome membranes. Elucidation of Wnt mobilization in the extracellular space has significant implications in the fields of Wnt signaling in both development and cancer.
Citation Format: Ying Yi Zhang, Ainsley Underhill, Liang Zhang, Jeffrey Wrana. Elucidating the mechanism of targeting WNT ligands to exosomes. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B67.
Abstract C06: Translation of isoform-level gene signature into robust diagnostic assay for glioblastoma subtyping
Authors: Bi Yingtao , Pal Sharmistha , Macyszyn Luke , O'Rourke Donald , Davuluri Ramana 
Published: August 2014

Abstract
Abstract: Translating the molecular signatures from classification strategies into robust diagnostic assays is essential for cancer therapy guidance and prognosis determination. To develop a clinically applicable molecular stratification assay for Glioblastoma multiforme (GBM) with significant prognostic value, we designed a novel classification system based on isoform-level gene expression profiles; an avenue unexplored for diagnostic and prognostic use. Using isoform-level expression clustering of The Cancer Genome Atlas (TCGA) samples, we identified four GBM subgroups with significant (p=0.0103) survival differences. A four-class classifier, built with 121 transcript-variants, assigns GBM patients' molecular subtype with 92% accuracy. The classifier was translated to a high-throughput RT-qPCR assay and validated on an independent cohort of 206 glioblastoma samples. We found that proneural patients have the worst prognosis except for younger patients (&lt;40 years), while a better prognosis is observed for neural group among older patients (≥40 years). The isoform-level classifier, transformed from a high-dimensional platform to a low-dimensional RT-qPCR platform, provides a quantitative and reproducible stratification of GBM patients with prognostic significance, a requirement towards personalized medicine. The resulting diagnostic assay from the classifier has immediate clinical implications towards prioritizing patients for standard care versus aggressive therapy regimen.
Citation Format: Yingtao Bi, Sharmistha Pal, Luke Macyszyn, Donald O'Rourke, Ramana Davuluri. Translation of isoform-level gene signature into robust diagnostic assay for glioblastoma subtyping. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C06.
Abstract C09: Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to cisplatin and poly (ADP-ribose) polymerase inhibition
Authors: Cavallo Francesca , Graziani Grazia , Antinozzi Cristina , Feldman Darren R. , Houldsworth Jane , Bosl George J. , Chaganti Raju S. K. , Moynahan Mary Ellen , Jasin Maria , Barchi Marco 
Published: August 2014

Abstract
Testicular Germ Cell Tumors (TGCT) and patient-derived cell lines are extremely sensitive to cisplatin and other interstrand cross-link (ICL) inducing agents. Nevertheless, a subset of TGCTs are either innately resistant or acquire resistance to cisplatin during treatment. Understanding the mechanisms underlying TGCT sensitivity/resistance to cisplatin as well as the identification of novel strategies to target cisplatin-resistant TGCTs have major clinical implications. Herein, we have examined the proficiency of five embryonal carcinoma (EC) cell lines to repair cisplatin-induced ICLs. Using γH2AX staining as a marker of double strand break formation, we found that EC cell lines were either incapable of or had a reduced ability to repair ICL-induced damage. The defect correlated with reduced Homologous Recombination (HR) repair, as demonstrated by the reduction of RAD51 foci formation and by direct evaluation of HR efficiency using a GFP-reporter substrate. HR-defective tumors cells are known to be sensitive to the treatment with poly(ADP-ribose) polymerase (PARP) inhibitor. In line with this observation, we found that EC cell lines were also sensitive to PARP inhibitor monotherapy. The magnitude of sensitivity correlated with HR-repair reduced proficiency and with the expression levels and activity of PARP1 protein. In addition, we found that PARP inhibition strongly enhanced the response of the most resistant EC cells to cisplatin, by reducing their ability to overcome the damage. These results point to a reduced proficiency of HR repair as a source of sensitivity of ECs to ICL-inducing agents and PARP inhibitor monotherapy, and suggest that pharmacological inhibition of PARP can be exploited to target the stem cell component of the TGCTs (namely ECs) and to enhance the sensitivity of cisplatin-resistant TGCTs to standard treatments.
Citation Format: Francesca Cavallo, Grazia Graziani, Cristina Antinozzi, Darren R. Feldman, Jane Houldsworth, George J. Bosl, Raju S. K. Chaganti, Mary Ellen Moynahan, Maria Jasin and Marco Barchi. Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to cisplatin and poly (ADP-ribose) polymerase inhibition. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C09.
Abstract C11: Molecular mechanism driving BMI1-induced melanoma metastasis
Authors: Ferretti Roberta , Lees Jacqueline A. 
Published: August 2014

Abstract
Malignant melanoma is one of the most aggressive human cancers, with a high potential for lethal metastasis and therapeutic resistance. The epigenetic chromatin regulator Bmi1 acts as a key component of the Polycomb Repressor Complex 1 (PRC1) and is a known oncogene. Various studies shown that BMI1 is highly expressed in many human hematopoietic malignancies and in different solid tumor types including prostate, breast, ovarian, colon, brain and lung cancer. Importantly, high Bmi1 expression is an excellent predictor of both metastatic progression and poor therapeutic response. Bmi1's role in tumor onset has been assessed using germline mutant mice showing that Bmi1 ablation efficiently suppress tumor development. This impaired tumorigenicity correlates with an impairment of the self-renewal and proliferative properties of tumor initiating cells, mainly due to Bmi1's repressive activity on the Ink4a/Arf tumor suppressor locus. Nevertheless, this function does not explain why Bmi1 is frequently upregulated in tumors nor Bmi1's role in tumor progression.
To evaluate Bmi1's contribution to melanoma progression, we upregulated Bmi1 in two different melanoma cell lines, a murine metastatic cell line and a poorly metastatic human cell line. We found that Bmi1 overexpression activates or increases invasive behavior of both cell lines, without enhancing their proliferative capacity. This finding allowed us to dissect Bmi1's oncogenic activity at later stages of tumorigenesis, in the absence of Bmi1's deregulation of cell proliferation. Our data show that Bmi1 significantly enhances in vitro cell movement and modulates adhesion. Bmi1 also protects cells from apoptosis induced by different stimuli and increases lung metastasis formation in vivo.
To characterize Bmi1-induced changes in gene expression, we have performed comparative deep sequencing of total RNA libraries generated from Bmi1 or GFP overexpressing cells. Gene ontology analysis revealed enrichment in cancer-relevant pathways that seem to be controlled by Bmi1, including cell movement, cell death and survival, tissue development and cell morphology. In particular, Bmi1 expression modulates the gene regulatory programs associated with EMT, TGFβ and the non-canonical Wnt pathways. We have identified a new Bmi1 target gene, poorly characterized, that seems to be responsible for Bmi1-induced melanoma progression. These data determine a causal role for Bmi1 in melanoma cell migration and establishment of distant melanoma metastasis.
Citation Format: Roberta Ferretti, Jacqueline A. Lees. Molecular mechanism driving BMI1-induced melanoma metastasis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C11.
Abstract C15: Therapeutic benefit of targeting ERK in mutant KRAS in pancreatic ductal adenocarcinoma (PDAC)
Authors: Hayes Tikvah K. , Neel Nicole F. , Chenard Melissa , Yeh Jen Jen , Samatar Ahmed , Der Channing J. 
Published: August 2014

Abstract
The limited success of anti-MEK and anti-RAF therapies with KRAS mutant cancers has been attributed, in part, to de novo or acquired resistance mechanisms that arise after prolonged treatment. A majority of resistance mechanisms involve kinome reprograming to reactivate ERK downstream of inhibitor activity. Therefore, we hypothesized that directly targeting ERK would be an effective method for overcoming these resistance mechanisms. To address this possibility, we evaluated the sensitivity of a panel of mutant KRAS pancreatic ductal adenocarcinoma (PDAC) cell lines to the highly selective SCH772984 ERK1/2 protein kinase inhibitor. First, we found that the anchorage-dependent growth of 6 of 12 cell lines were sensitive to SCH772984 treatment (IC50&lt;2 μM). Some sensitive PDAC lines were resistant to the AZD6244 MEK1/2-selective inhibitor, indicating different mechanisms of action of these two inhibitors. Second, we identified phospho-AKT as a potential biomarker for PDAC SCH772984 sensitivity. Third, we assessed the molecular basis for anchorage-dependent growth inhibition. After 72 h treatment, flow cytometry analyses indicated impaired cell cycle progression through G1. Additionally, we found increased apoptosis as measured by formation of cleaved caspase-3. Together these observations suggest that sensitivity is a result of both impaired cell cycle progression and induction of apoptosis. Surprisingly prolonged SCH772984 treatment (2 weeks) resulted in senescence, as sensitive lines stained positive for senescence-associated beta-galactocidase. Furthermore, we found that senescent cells induced p16 and lost phospho-RB two common markers associated with induction of senescence. Onset of senescence was dependent on the loss of total MYC protein expression. Finally, we found that treatment with SCH772984 reduced tumorigenic growth in an in vivo xenograft mouse model. Our ongoing studies include determining the mechanisms of inhibitor resistance. In summary, our findings suggest that targeting ERK will be therapeutically beneficial for the treatment of KRAS mutant PDAC.
Citation Format: Tikvah K. Hayes, Nicole F. Neel, Melissa Chenard, Jen Jen Yeh, Ahmed Samatar, Channing J. Der. Therapeutic benefit of targeting ERK in mutant KRAS in pancreatic ductal adenocarcinoma (PDAC). [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C15.
Abstract C16: Mapping synthetic vulnerabilities in non-small cell lung cancer
Authors: Kim Hyun Seok , Mendiratta Saurabh , Kim Jiyeon , Pecot Chad Victor , Larsen Jill E. , Zubovych Iryna , Seo Bo Yeun , Kim Jimi , Eskiocak Banu , Chung Hannah , McMillan Elizabeth , Wu Sherry , Brabander Jef De , Komurov Kakajan , Posner Bruce A. , Brekken Rolf , Sood Anil K. , Deberardinis Ralph J. , Roth Michael G. , Minna John D. , White Michael A. 
Published: August 2014

Abstract
Diversity in the genetic lesions that drive cancer initiation and progression is extreme. This diversity exists not only among tumors from different patients, but also among cancer cells within the same patient. This nefarious complexity is, in large measure, responsible for the capacity of this disease to evade current best efforts for effective therapy. “Personalized medicine” has been proposed in response to this conundrum as a mechanism to tailor cancer treatment to a specific tumor's genetic and epigenetic characteristics. However, selection of appropriate treatment is dramatically limited by the paucity of appropriate drugs and by the difficulty of linking treatment options to the appropriate patients. The challenge is to identify authentic intervention targets for development of an appropriately diverse cohort of therapies to contend with disease heterogeneity. We are addressing this challenge by a focused investigation of common vulnerabilities that arise as a consequence of oncogene expression and tumor evolution. Here we will describe a cancer intervention discovery pipeline using parallel genetic and chemical perturbations within an extensive panel of cell lines representative of the molecular lesions detected in lung cancer by national and international cancer genome sequencing efforts. We have found that current first line targeted therapies are discoverable within this panel together with the enrollment biomarkers required to stratify patient treatment regimens. Further, we have found that new genetic and chemical vulnerabilities can be revealed that are linked to recurrent mutations in lung cancer patients that are not currently “actionable”. We are leveraging this approach to stratify lung cancer subtypes and elaborate intervention targets that are linked to those subtypes by robust molecular discriminators.
Note: This abstract was not presented at the conference.
Citation Format: Hyun Seok Kim, Saurabh Mendiratta, Jiyeon Kim, Chad Victor Pecot, Jill E. Larsen, Iryna Zubovych, Bo Yeun Seo, Jimi Kim, Banu Eskiocak, Hannah Chung, Elizabeth McMillan, Sherry Wu, Jef De Brabander, Kakajan Komurov, Bruce A. Posner, Rolf Brekken, Anil K. Sood, Ralph J. Deberardinis, Michael G. Roth, John D. Minna, Michael A. White. Mapping synthetic vulnerabilities in non-small cell lung cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C16.