bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2424: Genomic landscape of aggressive tumor subtype in MYCN-non-amplified neuroblastoma
Authors: Ohira-Ichikawa Miki 
Published: July 2016

Abstract
Neuroblastoma is known to exhibit wide ranges of clinical phenotypes, from spontaneous regression to highly resistant to chemotherapy. One of the challenges in the clinic is to develop suitable therapeutic strategies for the intermediate risk-type of patients (stage 3 or 4 without MYCN amplification) whose prognosis sometimes tends to be poor in terms of long-term follow-up (10 years survival rate was 51% in our database, n = 161). To identify key biological pathways involved in the unfavorable phenotypes in this patient group, we have analyzed 63 primary tumors (dead:32, alive:31) without MYCN amplification nor ALK alteration by integrated genomic analyses such as array CGH, whole exome sequencing (SureSelect XT Human All Exon V4, average read depth:157, x20 coverage:95%), RNA sequencing, as well as Methylome profiling (Infinium HumanMethylation450 BeadChip). By using the Karkinos and ANNOVAR software, we found so far 816 non-synonymous somatic single nucleotide variations (SNVs) in coding exons in total (approximately 20 per tumor in average) and number of alterations in each tumor strongly correlated with age at diagnosis (p&lt;0.0001) and patient prognosis (p = 0.0077). Recurrent somatic SNVs (n = 2 to n = 5) were found in 66 genes, 19 of those were involved only in the tumors from the 24 patients with poor outcome. Gene Ontology and pathway analysis (GeneMANIA) using the 66 genes showed that mutations occurred in the features including cytoskeleton, ion channel and extracellular matrix were significantly correlated with patient survival of the 63 MYCN-non-amplified tumors with logrank p-values of 0.0039, 0.0482 and 0.0011, respectively. ATRX mutations were observed in four tumors (6.3%), all of them were occurred in patients with unfavorable phenotypes (3 dead, 1 alive but relapsed twice). By methylome signature, the 63 tumors were subdivided into at least three clusters, which also showed strong correlation with patient prognosis (cluster-1 vs. cluster-2 and -3, p = 0.0368). Unfavorable cluster-2 and -3 exhibited hyper-methylation phenotypes in CpG islands and the former was quite similar to that of MYCN-amplified tumors. Thus, these prognosis-related genomic features could be useful markers for risk classification and help understanding molecular mechanism for aggressive phenotypes of MYCN-non-amplified neuroblastomas.
Citation Format: Miki Ohira-Ichikawa. Genomic landscape of aggressive tumor subtype in MYCN-non-amplified neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2424.
Abstract 2445: Cytoplasmic mislocalization of p27 promotes metastasis and its autoantibody correlates with prognosis in osteosarcoma
Authors: Nakka Manjula , Li Yiting , Kelly Aaron J. , Lau Ching C. , Krailo Mark , Barkauskas Donald A. , Hicks John , Man Tsz-Kwong 
Published: July 2016

Abstract
Development of metastasis is the major cause of death in osteosarcoma, which is the most common malignant bone tumor in children and young adults. However, detection of metastasis relies solely on imaging techniques and targeted treatments of metastatic patients are still not available to improve the dismal outcome. Using an immunoproteomic approach, we identified that p27 autoantibody was significantly elevated in the plasma of high-risk osteosarcoma patients. Results of immunohistochemistry showed that cytoplasmic mislocalization of p27 occurred in a majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 and shRNA-mediated gene silencing promoted and inhibited, respectively, the migration and invasion of osteosarcoma cells. Additionally, a mutation in S10 or T198, but not T157, phosphosite abolished the pro-migration and invasion phenotypes of cytoplasmic p27, possibly through a RhoA-related mechanism. Furthermore, mice injected with cells carrying cytoplasmic p27 increased the development of pulmonary metastasis when compared to an empty vector control. Lastly, using a large cohort of serum samples (n = 233), we showed that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival of osteosarcoma (p &lt; 0.05). Together, our results suggest that the circulating p27 autoantibody can be used as a prognostic biomarker at diagnosis and cytoplasmic mislocalization of p27 is a frequent event in osteosarcoma, which can promote tumor cell motility and invasiveness as well as metastasis formation. Targeting specific p27 phosphorylations may provide a novel therapeutic approach for osteosarcoma patients with metastasis.
Citation Format: Manjula Nakka, Yiting Li, Aaron J. Kelly, Ching C. Lau, Mark Krailo, Donald A. Barkauskas, John Hicks, Tsz-Kwong Man. Cytoplasmic mislocalization of p27 promotes metastasis and its autoantibody correlates with prognosis in osteosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2445.
Abstract 2449: Hedgehog pathway inhibition sensitizes embryonal rhabdomyosarcoma to standard chemotherapy
Authors: Manzella Gabriele , Kottarathil Tina , Schaefer Beat W. 
Published: July 2016

Abstract
Hedgehog (Hh) is one of the key pathways orchestrating embryonic development as well as regulating homeostasis of postnatal organs. Perturbation of Hh signaling activity is associated with the onset of different childhood cancer entities such as embryonal rhabdomyosarcoma (eRMS). According to this, previous findings from our laboratory revealed that the tumor initiating populations (TIPs) of eRMS retain high activity of the pathway, which boosts their tumorigenic potential and self-renewal ability. Moreover, TIPs are well known to be responsible for seeding recurrent tumors following standard chemotherapy. This phenomenon might explain the failure of cytotoxic drugs in high-risk eRMS patients for whom conventional therapeutic approaches remain inadequate.
Therefore, in this study we investigated the role of Hh pathway in the context of chemoresistance. We established several patient-derived xenograft (PDX) models and primary cells derived from diagnostic and relapsed tumor specimens. Histological and immunofluorescence analysis confirmed that both cellular and patient heterogeneity were preserved in our cohort. Interestingly, we found that Hh target genes were significantly upregulated in chemoresistant PDX tumors and demonstrated that the use of Hh antagonists could significantly sensitize eRMS cells toward debulking drugs such as doxorubicin, actinomycin and vincristine. Ongoing experiments aim at confirming these results in cells with selective knock- out of components of Hh pathway as well as at elucidating if chemotherapy might induce a selection of resistant clones or a transition of sensitive cancer cells toward a resistant phenotype with high Hh pathway activity.
In conclusion, our data indicate that inhibition of Hh signaling might represent a promising strategy to enhance the therapeutic window of standard cytotoxic agents.
Citation Format: Gabriele Manzella, Tina Kottarathil, Beat W. Schaefer. Hedgehog pathway inhibition sensitizes embryonal rhabdomyosarcoma to standard chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2449.
Abstract 2450: MYCN and TFAP4 promote neuroblastoma malignancy by cooperating in the regulation a subset of target genes involved in cancer cell growth and metastasis
Authors: Xue Chengyuan , Yu Denise M. , Gherardi Samuele , Koach Jessica , Milazzo Giorgio , Gamble Laura , Liu Bing , Russell Amanda , Liu Tao , Cheung Belamy B. , Marshall Glenn M. , Perini Giovanni , Haber Michelle , Norris Murray D. 
Published: July 2016

Abstract
Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4), which plays important roles in cancer progression, has been reported to be a direct transcriptional target of MYC. In this study, we have shown that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome and furthermore that siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells impaired migration and colony formation, and led to an increased proportion of cells in G1/S phase of the cell cycle. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that TFAP4 expression is positively regulated by MYCN through direct promoter binding. In addition, when MYCN was overexpressed in neuroblastoma cells, TFAP4 was required for the observed increase in cell migration. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study unveils a complex regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying relevant therapeutic targets for aggressive forms of this disease.
Citation Format: Chengyuan Xue, Denise M. Yu, Samuele Gherardi, Jessica Koach, Giorgio Milazzo, Laura Gamble, Bing Liu, Amanda Russell, Tao Liu, Belamy B. Cheung, Glenn M. Marshall, Giovanni Perini, Michelle Haber, Murray D. Norris. MYCN and TFAP4 promote neuroblastoma malignancy by cooperating in the regulation a subset of target genes involved in cancer cell growth and metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2450.
Abstract 2506: Citral reduces breast tumor growth by inhibiting cancer stem cell marker ALDH1A3
Authors: Thomas Margaret L. , De Antueno Roberto , Coyle Krysta , Cruickshank Brianne , Giacomantonio Michael , Duncan Roy , Giacomantonio Carman , Marcato Paola 
Published: July 2016

Abstract
Breast cancer stem cells (CSCs) can be identified by increased Aldefluor activity which is primarily due to aldehyde dehydrogenase 1A3 (ALDH1A3) expression. In addition to being a CSC marker, ALDH1A3 regulates genes expression via inducing retinoic acid (RA) signaling and plays an important role in mediating progression of cancers, including breast, melanoma, lung and glioblastoma. Therefore, ALDH1A3 represents a novel druggable anti-cancer target of interest. There are no currently characterized inhibitors of the ALDH1A3 isoform, so twelve general ALDH inhibitors were tested for their effectiveness in targeting ALDH1A3 activity. Ability to directly inhibit ALDH activity was quantified with the Aldefluor assay on a patient tumor xenograft and on breast cancer cell lines with known ALDH isoform activity. Inhibition of RA signaling was quantified by measuring expression of the RA-inducible genes RARRES1 and RARβ. To investigate the anti-cancer properties of these compounds, apoptosis was quantified with the annexin V assay. Citral significantly reduced ALDH1A3- and ALDH2-associated Aldefluor activity in breast cancer cell lines and also reduced Aldefluor activity of a patient-derived xenograft. Citral reduced expression of RA-inducible genes through reducing ALDH1A3 activity. Citral induced apoptosis in vitro in an ALDH-independent manner in breast cancer cell lines and reduced proliferation in the MDA-MB-231 breast cancer cell line. Nanoparticle (NP)-encapsulated citral was generated for in vivo use and administered intravenously to female NOD/SCID mice harbouring MDA-MB-231 ALDH1A3-overexpression tumors. 10mg/kg NP-citral significantly decreased the growth of ALDH1A3-driven MDA-MB-231 tumors. Nanoparticle-encapsulated citral shows promise as an adjuvant therapy for patients with tumors that have a large population of high-ALDH1A3 CSCs.
Citation Format: Margaret L. Thomas, Roberto De Antueno, Krysta Coyle, Brianne Cruickshank, Michael Giacomantonio, Roy Duncan, Carman Giacomantonio, Paola Marcato. Citral reduces breast tumor growth by inhibiting cancer stem cell marker ALDH1A3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2506.
Abstract 2508: A red-shifted fluorescent substrate for aldehyde dehydrogenase, AldeRed 588-A, for labeling viable ALDH-positive cells
Authors: Asbrock Nick , Chu Vi , Pomper Martin 
Published: July 2016

Abstract
Normal and cancer stem cells can be isolated based upon the enzymatic activity of aldehyde dehydrogenase I (ALDH1), a detoxifying enzyme responsible for oxidation of hazardous aldehyde byproducts. ALDH1 has been used to isolate cancer stem cells from various human malignancies including bladder, breast, cervical, colon, head and neck, liver, lung, pancreas, prostate and ovary. Currently, the ALDEFLUOR assay, is the only commercially available reagent for ALDH detection in live cells. The substrate used in this assay primarily emits in the green region of the electromagnetic spectrum (512nm). For researchers with valuable cell and transgenic animal models in which the target gene of interest has been tagged with eGFP, ALDEFLUOR therefore cannot be used. Selection of cells positive for aldehyde dehydrogenase (ALDH) activity from a green fluorescent background is thus difficult with existing reagents. We now describe a red-shifted fluorescent substrate for ALDH, AldeRed 588-A, that provides additional flexibility for utilizing ALDH as a marker for stem cell and cancer stem cell isolation. The activity of AldeRed 588-A was compared with the ALDEFLUOR reagent and demonstrated similar ability to fractionate ALDHpos cells in a number of cell lines tested.
Citation Format: Nick Asbrock, Vi Chu, Martin Pomper. A red-shifted fluorescent substrate for aldehyde dehydrogenase, AldeRed 588-A, for labeling viable ALDH-positive cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2508.
Abstract 2516: TRIM8 modulates stem-like cells in glioblastoma
Authors: Zhang Changming , Subhas Mukherjee , Carol Tucker-Burden , Chau Monica , Kong Jun , Brat Daniel 
Published: July 2016

Abstract
Glioblastoma stem-like cells (GSC) contribute to rapid growth and clinical recurrence of these fatal tumors and are highly resistant to therapy. STAT3 is known to contribute to maintenance and proliferation of GSC. Here we report a novel protein known as Tri-partite Motif containing protein 8 (TRIM8) that modifies tumor growth through STAT3. TRIM8, previously referred to as “glioblastoma expressed ring finger protein” is expressed at equal levels in glioblastoma and normal brain samples, despite showing hemizygous deletion in 87% of cases in TCGA data. To uncover mechanisms, we knocked down TRIM8 in glioblastoma-derived neurospheres using sh-RNA and found that this reduced the levels of phosphorylated STAT3 (p-STAT3), C-MYC and SOX2. Overexpression of TRIM8 resulted in higher expression of p-STAT3, C-MYC, SOX2 and CD133. We also found that specifically blocking STAT3 in neurospheres by pharmacological inhibition reduced the expression of TRIM8. Conversely, upregulation of STAT3 induced by IL-6 results in increased expression of TRIM8. Together, our results indicate that TRIM8 could potentially regulate GSC by forming a positive feedback loop with STAT3.
Citation Format: Changming Zhang, Mukherjee Subhas, Tucker-Burden Carol, Monica Chau, Jun Kong, Daniel Brat. TRIM8 modulates stem-like cells in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2516.
Abstract 2519: A novel role for brachyury as a key regulator of sonic hedgehog signaling (Shh) and maintenance of stemness in gliomas
Authors: Kesanakurti Divya , Canella Alessandro , Xu Jihong , Puduvalli Vinay K. 
Published: July 2016

Abstract
Glioblastomas are the most common and aggressive form of adult primary brain tumors and are associated with a dismal prognosis. Accumulating evidences suggest that a subset of therapy-resistant cancer stem cells are responsible for recurrence in tumors targeting which may help in gliomas. We identified a significant overexpression of Brachyury (T-box transcription factor) in correlation with glioma histological grade when compared to non-tumor brain controls, with the highest expression being in grade IV gliomas. We also observed increased expression of Brachyury in several glioma cell lines and stem cells (GSCs) when compared to normal human astrocytes. Serum-induced differentiation of GSCs resulted in loss of Brachyury expression along with decreased stem-cell marker levels in these cells, which prompted us to study the potential role of Brachyury in glioma stemness and to delineate the underlying signaling mechanisms. Specific shRNA-mediated knockdown of Brachyury significantly decreased proliferation, migration and invasion in glioma cell lines. Brachyury suppression led to inhibition of sphere formation of GSCs and decreased stem cells marker expression including CD133, nestin and Nanog. Brachyury knockdown also inhibited the activation of sonic hedgehog (Shh) signaling and decreased Gli1 levels in these cells. On the other hand, stable overexpression of Brachyury resulted in the activation of Shh pathway and elevated stem cell marker expression in GSCs. Based on these in vitro findings, our future studies will be focused on determining the role of Brachyury in orthotopic tumor growth in vivo. In summary, our data reveals a novel role for Brachyury in the regulation of tumor invasiveness and stemness, and indicates a potential for therapeutic targeting of Brachyury in patients with gliomas.
Citation Format: Divya Kesanakurti, Alessandro Canella, Jihong Xu, Vinay K. Puduvalli. A novel role for brachyury as a key regulator of sonic hedgehog signaling (Shh) and maintenance of stemness in gliomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2519.
Abstract 2522: S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs
Authors: Chow KIn-Hoe , Park Hee Jung , George Joshy , Gallup Andrew D. , Neilson Eric , Yun Kyuson 
Published: July 2016

Abstract
Glioblastoma (GBM) is one of the most incurable human cancers, and the mesenchymal subtype of GBMs has the worst prognosis. The mesenchymal phenotype and glioma stem cells (GSCs) are associated with tumor recurrence and therapy resistance. While growing evidence suggests that tumor microenvironment modulates stemness and the mesenchymal phenotype, little is known about how these phenotypes are coordinately regulated. Here we report that S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs. First, we show that S100a4 is a novel marker and a regulator of GBM TICs. Using genetically engineered mice and patient derived GBM tumorspheres, we show that S100a4 expression is enriched in TICs and that S100a4 function is critical for self-renewal of these cells. Furthermore, we demonstrate that selective ablation of S100a4+ cells in vivo is sufficient to block tumor growth. Second, we show that S100A4 regulates expression of EMT regulators, SNAIL2 and ZEB1, in addition to master transcriptional regulators of the mesenchymal signature genes (CEBPB/D, RUNX1, FOSL2, and BHLHE40), suggesting that S100A4 is an upstream (master) regulator of mesenchymal transition in GBMs. Third, we show that acidosis, a common environmental stress in malignant tumors, induces S100A4 and epithelial-mesenchymal transition (EMT) regulator expression. Importantly, S100A4 is required for acidosis-induced EMT and mesenchymal transition. Consistently, S100A4 expression is strongly associated with the mesenchymal subtype of GBMs, and S100A4 is an independent prognostic indicator for the mesenchymal subtype GBM patient survival. In summary, we show that S100A4 is a critical node in the molecular network that controls glioma stem cells and the mesenchymal phenotype, and propose that targeting S100A4 may simultaneously suppress mesenchymal transition and stemness of glioma cells, particularly in stressful tumor environments.
Citation Format: KIn-Hoe Chow, Hee Jung Park, Joshy George, Andrew D. Gallup, Eric Neilson, Kyuson Yun. S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2522.
Abstract 2532: Alginate-based 3D system for the enrichment and culture of cancer stem cells
Authors: Simon Karen A. , Murikipudi Sylaja , Rogoff Harry A. , Li Chiang J. 
Published: July 2016

Abstract
Cancer stem cells (CSCs)—cancer cells which have the ability to undergo “self-renewal” are considered to be responsible for the recurrence and metastasis of tumors. The development of a culture system which can mimic aspects of the tumor microenvironment within the cancer stem cell niche is important to elucidate the mechanisms that underlie the growth and survival of CSCs and to identify compounds that can target and eliminate this highly malignant cell population.
Here we demonstrate the use of an alginate-based 3D cell culture as an in vitro system for enriching and maintaining the stemness properties of cancer cell lines. In this work, we used alginate gels as a three-dimensional (3D) matrix to culture cancer cell lines. Alginate is an ideal system for CSC because of its inertness and ability to provide a hypoxic environment essential for maintaining the stem-like properties of these cells. We found that cells cultured in the alginate 3D matrix have increased CSC-related gene expression and alterations in metabolic-related gene expression that are consistent with changes reported to occur in CSC that help them to maintain their drug resistant and invasive properties.
In order to be useful as a drug screening platform to identify CSC targeting agents, we verified that the high stemness characteristics of the cells cultured in the alginate 3D matrix can be maintained over multiple passages and many months of continuous culture. The CSC cultures in the alginate 3D matrix were found to be resistant to both conventional chemotherapy and targeted therapeutics, while remaining sensitive to CSC targeting agents BB608 and BB503. These results support the potential of the alginate 3D culture system in the enrichment and expansion of CSCs, and provide a reliable in vitro system for the development and evaluation of CSC-targeting agents.
Citation Format: Karen A. Simon, Sylaja Murikipudi, Harry A. Rogoff, Chiang J. Li. Alginate-based 3D system for the enrichment and culture of cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2532.