bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3863: A subset of poorly prognostic pediatric posterior fossa ependymomas exhibit lowered H3K27me3 and DNA hypomethylation and show epigenetic similarities with H3K27M mutant diffuse intrinsic pontine gliomas
Authors: Venneti Sriram , Bayliss Jill , Mukherjee Piali , Lu Chao , Jain Siddhant , Chung Chan , Martinez Daniel , Sabari Benjamin , Margol Ashley , Panwalkar Pooja , Paroloia Abhijit , Pekmezci Melike , Eachin Richard Mc , Cieslik Marcin , Tamrazi Benita , Garcia Benjamin , Rocca Gaspare La , Santi Mariarita , Lewis Peter , Hawkins Cynthia , Melnick Ari , Allis C David , Thompson Craig B. , Chinnaiyan Arul , Judkins Alexander R. 
Published: July 2017

Abstract
Pediatric posterior fossa ependymomas are poorly understood childhood brain tumors and have no effective treatments. The biology of these tumors is obscure as recent sequencing efforts suggest that they lack recurrent genetic alterations. A subset of these tumors termed PF-A ependymomas exhibits CpG-island hypermethylation implicating epigenetic alterations in their pathogenesis. Through comprehensive analyses of histone modification, we discovered global H3K27me3 reduction in a subset of these tumors. Tumors with lowered H3K27me3 showed many clinical and biologic similarities with PFA-ependymomas. Global reduction in H3K27me3 is likewise observed in pediatric gliomas that bear histone H3K27M mutations termed diffuse intrinsic pontine gliomas (DIPG) that also arise in the posterior fossa of young children. Analyses of ependymomas with reduced H3K27me3 and H3K27M mutant DIPGs showed many similarities in DNA methylation and enrichment of H3K27me3 in many genomic loci important for neuroglial specification. Combined integrative analysis of both tumor types uncovered common epigenetic deregulation of select factors that control radial glial biology and radial glia in the developing posterior fossa showed reduced H3K27me3. Finally, PF ependymomas with lowered H3K27me3 were more invasive radiologically and exhibited poor prognosis in three independent cohorts (P&lt;0.001 in all three cohorts, collective n&gt;300). These data have clinical implications for biomarker development and to inform epigenetic approaches to treat PF ependymomas.
Citation Format: Sriram Venneti, Jill Bayliss, Piali Mukherjee, Chao Lu, Siddhant Jain, Chan Chung, Daniel Martinez, Benjamin Sabari, Ashley Margol, Pooja Panwalkar, Abhijit Paroloia, Melike Pekmezci, Richard Mc Eachin, Marcin Cieslik, Benita Tamrazi, Benjamin Garcia, Gaspare La Rocca, Mariarita Santi, Peter Lewis, Cynthia Hawkins, Ari Melnick, C David Allis, Craig B. Thompson, Arul Chinnaiyan, Alexander R. Judkins. A subset of poorly prognostic pediatric posterior fossa ependymomas exhibit lowered H3K27me3 and DNA hypomethylation and show epigenetic similarities with H3K27M mutant diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3863. doi:10.1158/1538-7445.AM2017-3863
Abstract 3865: Targeting the epigenetic modifier HMGA2 in lethal adult and pediatric gliomas inhibits invasion, growth and tumorigenicity
Authors: Kaur Harpreet , Ali Sabeen Z. , Guo Huizi , Akhtarkhavari Sepehr , Rodriguez Fausto , Eberhart Charles G. , Raabe Eric H. 
Published: July 2017

Abstract
Glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are highly infiltrative, incurable adult and pediatric brain tumors characterized by the presence of tumor stem-like cells. Although GBM and DIPG have different epigenetic drivers, we found increased expression of an epigenetic modifier and stem cell factor HMGA2 in both tumors by immunohistochemistry and western blotting. HMGA2 is a DNA-binding protein that regulates transcription during normal embryogenesis and in cancer stem cells. We hypothesized that HMGA2 contributes to high grade glioma tumorigenicity through its ability to alter the transcription of many genes. Lentiviral short hairpin RNA (shRNA)-mediated reduction of HMGA2 in multiple patient-derived GBM cell lines significantly reduced invasion in transwell assay (shHMGA2 vs. shControl, P&lt;0.01). Similarly, shRNA mediated suppression of HMGA2 in DIPG cell lines reduced proliferation (BrdU incorporation), reduced invasion (transwell assay), inhibited clonogenicity (soft agar assay) and increased apoptosis (cleaved caspase-3 immunofluorescence, shHMGA2 vs. shControl, P&lt;0.001). Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug Netropsin significantly inhibited invasion (transwell assay), decreased proliferation (BrdU incorporation) and increased apoptosis of DIPG neurospheres (P&lt;0.01). Mice bearing orthotopic GBM xenografted cells transduced with HMGA2 shRNA lived significantly longer (108 days) compared to control shRNA (67.5 days, P&lt;0.0001 by log-rank analysis). To investigate the mechanism of HMGA2-mediated malignancy, we discovered high levels of CD44 (a known mediator of invasion and stemness) that correlated with high HMGA2 expression in DIPG and GBM tumors. Suppression of HMGA2 led to decreased CD44 expression while ectopic expression of HMGA2 increased CD44 expression in GBM cell neurospheres. Knockdown of CD44 in HMGA2-high GBM neurospheres reduced invasion (P&lt;0.01). Our studies suggest an oncogenic role of HMGA2 and its downstream effectors in gliomas and identify this important pathway as a potential therapeutic target. We conclude that minor groove binding agents similar to Netropsin may be effective agents for HMGA2-expressing pediatric and adult high grade gliomas.
Citation Format: Harpreet Kaur, Sabeen Z. Ali, Huizi Guo, Sepehr Akhtarkhavari, Fausto Rodriguez, Charles G. Eberhart, Eric H. Raabe. Targeting the epigenetic modifier HMGA2 in lethal adult and pediatric gliomas inhibits invasion, growth and tumorigenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3865. doi:10.1158/1538-7445.AM2017-3865
Abstract 3869: Cell surface vimentin targeted mAb 86C increases sensitivity to temozolomide mediated cell death in glioma stem cells
Authors: Noh Hyangsoon , Yan Jun , Gabrusiewicz Konrad , Li Shulin 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive brain tumor in pediatric patients. The current standard of care including radiation and chemotherapy is not effective in most patients due to multiple factors such as resistance and poor blood-brain barrier (BBB) penetration. The development of strategies to reduce resistance and to increase sensitivity to chemotherapy may ameliorate the problems. Glioma stem cells (GSCs) are considered the source of relapse and chemoresistance. Sensitization of temozolomide TMZ resistance in GSC is therefore integral for therapeutic efficacy. Our lab has discovered that cell surface vimentin (CSV) is presented on patient-derived GSCs. In this study, we demonstrate that the treatment of GSCs with anti-CSV antibody (86C) sensitizes them to TMZ. We found that the combination of 86C and TMZ induced additional antitumor effects in 8 out of 12 GSCs. Mechanistic study of the four resistance GSCs revealed slow re-surface rate of CSV from CSV- GSCs and low CSV expression on GSCs as possible contributing factors. GSCs with rapid CSV resurfacing from CSV- GSCs was more sensitive to combination treatment compared to GSCs with a slow recovering from CSV- GSCs. Furthermore, the metabolism study shows these four resistance cells have high intrinsic mitochondria activity compared to sensitive cells. The combination of TMZ with 86C may represent a valuable strategy to reverse GSC chemoresistance.
Citation Format: Hyangsoon Noh, Jun Yan, Konrad Gabrusiewicz, Shulin Li. Cell surface vimentin targeted mAb 86C increases sensitivity to temozolomide mediated cell death in glioma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3869. doi:10.1158/1538-7445.AM2017-3869
Abstract 3871: Modeling the chromatin and transcriptional landscape of MYC and MYCN driven neuroblastoma in zebrafish
Authors: Zimmerman Mark W. , He Shuning , Zhu Shizhen , Yang Song , Zhou Yi , Zon Leonard I. , Look A Thomas 
Published: July 2017

Abstract
Elevated expression levels of MYC family genes are frequently observed in human cancer cells and correlate with tumor aggressiveness and poor prognosis. In neuroblastoma 40% of all cases are high-risk, of which 20% harbor amplification of the MYCN proto-oncogene. In high-risk cases lacking MYCN gene amplification, high expression levels of c-MYC (MYC) are often present and are associated with unfavorable histology and a poor survival. Unlike MYCN amplification, which is frequently observed in the presence of segmental chromosomal aberrations, MYC overexpression is not associated with genetic abnormalities or somatic mutations. In order to study this newly defined subgroup, we have created a novel transgenic zebrafish model in which overexpression of MYC alone in the peripheral sympathetic nervous system (PSNS) drives early-onset neuroblastoma in nearly every fish by seven weeks of age. The tumors resulting from MYC overexpression arise in the interrenal gland, which is the fish counterpart of the adrenal medulla, and are histologically identical to human neuroblastoma. We next performed the Assay for Transposase Accessible Chromatin (ATAC) sequencing and RNA-seq to identify open chromatin regions that correlate with activation of gene transcription. Lineage specific genes essential for neuronal precursor cell identity, such as PHOX2B, HAND2, and TFAP2A are highly expressed in both MYC-expressing and MYCN-amplified human neuroblastoma cell lines and are actively transcribed in zebrafish models of MYC and MYCN driven neuroblastoma. Furthermore, these studies reveal shared and differential regulatory of effects of MYC relative to MYCN activity in maintaining the malignant phenotype of neuroblastoma in vivo. Additional insight into the mechanisms of aberrant transcriptional regulation will inform the future design and use of therapeutic strategies targeting transcription in this high-risk malignancy of childhood.
Citation Format: Mark W. Zimmerman, Shuning He, Shizhen Zhu, Song Yang, Yi Zhou, Leonard I. Zon, A Thomas Look. Modeling the chromatin and transcriptional landscape of MYC and MYCN driven neuroblastoma in zebrafish [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3871. doi:10.1158/1538-7445.AM2017-3871
Abstract 3873: Novel non-genetic mechanisms drive rhabdomyosarcoma tumorigenesis
Authors: McEvoy Justina , Dyer Michael , Chen Xiang 
Published: July 2017

Abstract
Most pediatric solid tumors originate from perturbations during development, however the mechanisms that drive these disruptions and promote tumor progression are still poorly understood. We believe that epigenetic deregulation of cancer genes and developmental pathways is a common driver in pediatric cancers, especially those with a low mutation rate. To test this novel idea, we are focusing on rhabdomyosarcoma (RMS), a developing muscle tumor with striking genetic differences between two of the major subtypes. We hypothesize that differential epigenetic deregulation of differentiation programs and cancer genes between the major subtypes are essential for tumorigenesis. Indeed, our preliminary integrative analysis reveal distinct epigenetic landscapes between the two subtypes particularly at the loci of HOX cluster genes A-C, including an oncogenic HOXC long non-coding RNA (lncRNA) called HOTAIR. Knockdown of HOTAIR led to derepression of HOXD10, a candidate tumor suppressor, and a decrease in RMS proliferation, migration, and invasion. Thus, we believe HOX gene deregulation is required for tumorigenesis, and their implication in several adult cancers suggests this currently unappreciated mechanism is likely to be more broadly relevant. In addition, we identified a group of RMS specific novel lncRNAs, of which one demonstrates an essential role in cell survival. Our innovative approach to integrate epigenetic data sets from tumor types with varying genetic differences shed light on the mechanisms that drive tumorigenesis, which may lead to identifying previously unknown potential therapeutic targets. Since current therapeutic options have not changed over the last twenty-five years, these data will especially provide a strong translational impact for children with RMS, whose survival outcomes are less than 20% in the case of metastatic disease.
Note: This abstract was not presented at the meeting.
Citation Format: Justina McEvoy, Michael Dyer, Xiang Chen. Novel non-genetic mechanisms drive rhabdomyosarcoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3873. doi:10.1158/1538-7445.AM2017-3873
Abstract 3881: The expression of CD98hc might be a marker of radiation resistance in HNSCC
Authors: Kawasaki Yohei , Omori Yasufumi 
Published: July 2017

Abstract
Introduction: Head and Neck squamous cell carcinoma(HNSCC) represents an aggressive malignancy. Although new advanced therapeutic strategies have been applied to date, the 5-year survival rate have not been considerably improved. Generally speaking, high radio-sensitive HNSCC has good prognosis, however, there are radio-resistant HNSCC. Recently, Sanne et al, have reported CD98 is one of the marker of Cancer Stem Cell. Moreover, the over expression of CD98hc is high associated with different cancers including the colon cancer, renal cancer. CD98 is heterodimeric protein that comprises a heavy chain and a light chain. The CD98 heavy chain is type 2 linkage to one of 6 amino acid transporters. We hypothesize that irradiation may contribute to overexpression of CD98hc and expansion Cancer Stem Cell population in HNSCC.
Methods:cell culture: Ho-1-u-1(Mouth floor), Sa3(Gingiva), HSC2, HSC3,HSC4(tongue) were used for this experiment. These cell lines were exposed to 60 Gy (2Gy/day) to establish stable cell lines to radiation.Flow cytometry: For analysis of CD98-positive fraction, cell pellets were incubated with FITC-conjugated anti-human CD98hc mAb at the dilution of 1:11 at 4°C for 15min.Sphere formation assay: Cells were cultured in a serum-free medium. 1x104 cells were seeded in 80μl of serum free RPMI1640 medium. The recipe of which was mentioned above. Containing 1.0% agar on 100μl of a solidified serum free RPMI1640 was poured on the top of each well. The cells were incubated for 20 days in the same atomosphere as that for the monolayer culture.Migration Assay: Radius 24 well Cell Migration (Cell Biolabs, INC.) were purchased. The experiment was conducted according to the decided plotocol.
Result: In radiation resistant cells, spindle-shaped and large cytoplasmic cells were founded. After irradiation, the expression of CD98hc increased in all cell lines. In Ho-1-u-1, the population was divided into two distinct subpopulations showing a higher and a lower expression of CD98hc. Irradiated cancer cells exhibit an efficient ability to developed numerous large sphere. Irradiation had enhanced self-renewal of Cancer Stem Cells. Cell motility was higher in radio-resistant cells than their parental cells.
Conclusion: Radio-resistant cells overexpressed CD98hc. In other words, CD98hc may be a marker of radiation resistance. Since incomplete radiation therapy can expand Cancer Stem Cell population, so elucidation of mechanism of radiation resistance will improved radiotherapy. CD98hc might be the target for more efficient treatment.
Citation Format: Yohei Kawasaki, Yasufumi Omori. The expression of CD98hc might be a marker of radiation resistance in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3881. doi:10.1158/1538-7445.AM2017-3881
Abstract 3884: A tumor stem cell marker DCLK1 promotes hepatocellular carcinoma by regulating β-catenin, EMT and clonogenic properties of hepatocytes
Authors: Ali Naushad , Nguyen Charles B. , Chandrakesan Parthasarathy , May Randal , Dhanasekaran Danny , Bronze Michael S. , Houchen Courtney W. 
Published: July 2017

Abstract
Introduction: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide with a 5-year survival rate of &lt;15%. Chronic viral hepatitis, NASH, and cirrhosis are major risk factors for the HCC development. Thus, HCC represents a major public health issue worldwide. Currently, sorafenib is the only FDA-approved drug used for HCC treatment. Unfortunately, it increases patient's survival by only 3 months. Tumor stem cells (TSCs) are likely responsible for resistance to chemotherapy, relapse, and metastasis. We have demonstrated that a TSC marker, doublecortin-like kinase (DCLK1), is induced during hepatic injury, cirrhosis and HCC and its overexpression in HCC patient’s liver significantly reduces survival. Therefore, understanding of the mechanism(s) hepatic TSCs regulation is important for the development of effective therapy against HCC.
Methods: Hepatoma Huh7 cells and primary human hepatocytes were infected with lentiviruses expressing recombinant RFP-DCLK1 fusion protein. The RFP-DCLK1-positive cells were isolated using FACS and subjected to immunofluorescence confocal microscopy, clonogenic assay, Western blot and xenograft in mice.
Results: DCLK1-overexpressing human hepatocytes formed spheroids but not the control cells. DCLK1 overexpression induced accumulation of active β-catenin in the perinuclear and nuclear regions in Huh7 cells with concomitant increase in c-Myc. The DCLK1-negative cells lacked active β-catenin and total β-catenin was observed only in their cell membranes. Hepatic β-catenin mRNA levels were unaffected during various stages of HCC. Analysis of HCC patients’ liver tissues (n= 369) suggested that elevated DCLK1 mRNAs expression significantly correlates with increased levels of MMP2, vimentin, Zeb2, Twist1 and VEGF-C which are involved in epithelial-to-mesenchymal transition (EMT) and tumor invasion. Huh7-derived tumors also exhibited high level expression of these factors.
Conclusions: These observations suggest that DCLK1 induces tumor/cancer stem cell-like properties and EMT in liver cells. DCLK1 appears to enhance active β-catenin levels and its cellular localization to the nucleus. Thus, the DCLK1 represents an important target for HCC therapy.
Citation Format: Naushad Ali, Charles B. Nguyen, Parthasarathy Chandrakesan, Randal May, Danny Dhanasekaran, Michael S. Bronze, Courtney W. Houchen. A tumor stem cell marker DCLK1 promotes hepatocellular carcinoma by regulating β-catenin, EMT and clonogenic properties of hepatocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3884. doi:10.1158/1538-7445.AM2017-3884
Abstract 3896: Exosomes derived from CD133+ hepatocellular carcinoma (HCC) cell promote the acquisition of stem cell-like properties of the targeted HCC cell via the Akt/GSK 3β/Snail and cyclin D1 pathways
Authors: Guo Pengyi , Yu Haitao , Xie Xiaozhai , Wang Yi , Chen Gang 
Published: July 2017

Abstract
Backgrounds and Aims: Liver cancer stem cells are closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC). However, the mechanism underlying the reciprocity between liver cancer stem cells and HCC cells in the tumor microenvironment remains unclear. Exosomes act as natural shuttles to deliver bioactive molecules that alter the behavior of the recipient cells, offering a new means of cell-cell communication for physiological and pathological processes in the liver. This study aimed to clarify whether the exosomes derived from the liver stem cells could facilitate the acquisition of stem cell-like properties of the adjacent HCC cells, thereby promoting the malignant process of HCC.
Methods: CD133+ liver cancer stem cells were isolated from the highly invasive HCC-LM3 cells or tumor tissues of HCC patients using flow cytometry and were identified using qPCR and immunofluorescence. The exosomes from CD133+ liver cancer stem cells were identified using CD133 and other stem cell markers, and they were then used to treat HepG2 and Hep3B cells. The cell viability, invasion ability, sphere formation and tumorigenesis abilities of the treated HepG2 and Hep3B cells were analyzed to reveal the effect of CD133+ exosomes, and the underlying molecular mechanism was further explored.
Results: CD133+ liver cancer stem cells were successfully isolated from HCC-LM3 cells and HCC patients’ tumor tissues, which were able to release CD133+ exosomes. The intake of CD133+ exosomes promoted the putative stem cell phenotype of Hep3B and HepG2 cells, as evidenced by significantly enhanced cell proliferation, invasion and sphere formation abilities in vitro and tumorigenesis in vivo. In additional, we found that CD133+ exosomes activated the PI3K/Akt/GSK3β/Snail and cyclin D1 pathway, thereby reducing the expression of E-Cadherin and promoting the epithelial-mesenchymal transition (EMT) of HCC cells.
Conclusions: Our results suggest that exosomes derived from CD133+ HCC cells can change the malignant behavior and promote the acquisition of stem cell-like properties of targeted HCC cells via the Akt/GSK 3β/Snail and cyclin D1 pathways.
Note: This abstract was not presented at the meeting.
Citation Format: Pengyi Guo, Haitao Yu, Xiaozhai Xie, Yi Wang, Gang Chen. Exosomes derived from CD133+ hepatocellular carcinoma (HCC) cell promote the acquisition of stem cell-like properties of the targeted HCC cell via the Akt/GSK 3β/Snail and cyclin D1 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3896. doi:10.1158/1538-7445.AM2017-3896