bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4844: CRISPR-generated BAP1 knockdown in uveal melanoma cell lines affects organotropism
Authors: Mahal Katharina , Brooks Kelly , Mandal Amit , Smith Matthew , Dhomen Nathalie , Marais Richard 
Published: July 2017

Abstract
Uveal melanoma (UM), a genetically distinct subtype of melanoma, arises from melanocytes located in the uveal tract of the eye, and is the most common intraocular cancer in adults. Clinically evident metastasis occurs in about 50% of patients, often several years after successful treatment of the primary tumour, with secondary disease occurring predominantly in the liver. In most cases surgical resection is not possible, and there are currently no effective chemotherapeutic treatments available once the metastatic disease has developed. Loss of the tumor suppressor and chromatin modifier BAP1 (BRCA1-associated protein 1) is linked with poor prognosis and high risk for developing liver metastasis. However, our knowledge about the processes involved in UM metastasis and the mechanisms that enable metastatic growth preferentially in the liver is limited.
We recently described a panel of isogenic BAP1 knockout/knockdown UM cell lines generated by CRISPR technology, which allowed us to study the cellular effects of BAP1 loss in comparison to parental UM cell lines. In mouse xenograft studies we were able to show that BAP1-loss of function (LOF) promoted metastatic growth preferentially in the liver, while the parental cells metastasized mainly to lymph nodes and lung.
A possible explanation for the observed liver tropism could lie in the alteration of protein secretion or receptor expression patterns upon BAP1 knockout that may result in an increased sensitivity to liver specific growth factors or cytokines. We are currently investigating gene expression and protein alterations resulting from BAP1 knockdown, and the reciprocal signaling between the CRISPR cell line pairs and liver cells such as hepatocytes and hepatic stellate cells in co-culture experiments. These studies will reveal a potential mechanism by which loss of BAP1 function mediates liver tropism in vivo and potentially provide new therapeutic avenues for patients at high risk of metastatic UM disease.
Citation Format: Katharina Mahal, Kelly Brooks, Amit Mandal, Matthew Smith, Nathalie Dhomen, Richard Marais. CRISPR-generated BAP1 knockdown in uveal melanoma cell lines affects organotropism [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 4844. doi:10.1158/1538-7445.AM2017-4844
Abstract 4845: Induction of aldolase C expression by NME1 may mediate metastasis suppressor activity in malignant melanoma
Authors: Pamidimukkala Nidhi , Leonard Katie , McCorkle Joseph , Zhang Qingbei , Mahurkar Anup , Shetty Amol , Kaetzel David 
Published: July 2017

Abstract
Although the metastasis suppressor activity of NME1 has been demonstrated in a number of settings of
human cancer, the underlying molecular mechanisms are not well understood. NME1 has two known
enzymatic activities, nucleoside diphosphate kinase (NDPK) and a 3’ to 5’ exonuclease. To determine
the relative contribution either of these activities has on the metastasis suppressor function of NME1,
our lab previously generated site directed mutants to abrogate one or both of the enzymatic activities
(Ma et al., 2004). These studies showed that disrupting the 3’ to 5’ exonuclease activity with the point
substitutions glutamate5-to-alanine (E5A) and lysine12-to-glutamine (K12Q) also significantly compromised
the metastasis suppressor function of NME1 (Zhang et al., 2011). To identify genes that are regulated by
NME1 and potentially modulate its metastasis suppressor activity, we compared the gene expression
profile induced by forced expression of wild-type NME to those obtained with the E5A and K12Q mutants.
Using the human Exon 1.0 Affymetrix microarray , we identified 13 genes whose expression was
modulated by wild-type NME1 expression, but not by the suppressor-deficient mutants, which were
designated as metastasis suppressor signature (MSS) genes. We are currently refining the list to genes
that have the highest clinical relevance through observing expression profiles of the MSS genes in
clinical datasets. Preliminary results of unsupervised hierarchal clustering of GEO melanoma dataset
GSE8401 showed that expression of the MSS gene, aldolase C (ALDOC), was significantly lower in a
subset of metastatic melanoma lesions compared to primary melanomas. Western blot and qPCR
analysis confirm that NME1 induces expression of ALDOC in both WM793 and M14 melanoma cell lines,
and that induction of ALDOC is dose-responsive to NME1 expression as observed in the WM1158
metastatic melanoma cell line. Further, NME1 induction of ALDOC is specific compared to the ALDOA
and ALDOB isoforms. Recent studies have indicated aldolase isoforms can modulate motile and invasive
phenotypes of cancer cells (Li et al., 2015 & Hu et al., 2016), suggesting regulation of ALDOC expression
may represent a key mechanism underlying the metastasis suppressor function of NME1. Current work
is focused on measuring the impact of NME1-induced expression of ALDOC on the metastatic potential
of melanoma cells in culture and in vivo.
Citation Format: Nidhi Pamidimukkala, Katie Leonard, Joseph McCorkle, Qingbei Zhang, Anup Mahurkar, Amol Shetty, David Kaetzel. Induction of aldolase C expression by NME1 may mediate metastasis suppressor activity in malignant melanoma [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 4845. doi:10.1158/1538-7445.AM2017-4845
Abstract 4846: The metastasis suppressor NME1 is recruited to DNA double strand breaks
Authors: Puts Gemma S. , Jarrett Stuart G. , Snyder Devin , Vincent Richard , Wang Ying , Leonard Katie , Portney Ben , Rassool Feyruz , Zalzman Michal , Kaetzel David M. 
Published: July 2017

Abstract
NME1 is a potent suppressor of metastasis, and reduced expression has been associated with aggressive melanoma. The nucleoside diphosphate kinase and 3’-5’ exonuclease (3’-5’ EXO) activities of NME1 protein both contribute to its metastasis suppressor activity. 3’-5’ exonucleases are important for proofreading during DNA repair and synthesis, suggesting a potential role for NME1 in maintenance of genomic stability in melanoma. Although impairment of DNA repair activity has been implicated in melanoma risk, its contribution to melanoma initiation and progression is not well understood. We have shown previously that both enzymatic activities of NME1 are critical for repair of UV-induced DNA damage via nucleotide excision repair. In the current study, chromatin immunoprecipitation was used to demonstrate recruitment of NME1 to DNA double-strand breaks (DSBs), representing the first evidence of direct recruitment of NME1 to sites of DNA damage. Induction of DSBs with gamma irradiation (γ-IR) or bleomycin promoted rapid physical association of NME1 with γH2AX, ATM, NBS1 and RAD50. In addition, treatment of melanoma cells with γ-IR triggered a physical association of NME1 with XRCC4, an effector of the non-homologous end-joining (NHEJ) pathway. We are currently investigating whether knockout of NME1 induces a switch from NHEJ to the homologous recombination (HR) pathway, a slower but higher fidelity form of DSB repair, using plasmid repair assays. We are also using plasmid rescue to study the role of NME1 on the fidelity of NHEJ repair. Overall, our study indicates for the first time direct participation of NME1 in a molecular mechanism of DSB repair in both normal and transformed cells. In addition, these data suggest a novel mechanism of metastasis suppressor function for NME1, with loss of NME expression in tumor cells conferring genetic instability and enhanced metastatic potential.
Citation Format: Gemma S. Puts, Stuart G. Jarrett, Devin Snyder, Richard Vincent, Ying Wang, Katie Leonard, Ben Portney, Feyruz Rassool, Michal Zalzman, David M. Kaetzel. The metastasis suppressor NME1 is recruited to DNA double strand breaks [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 4846. doi:10.1158/1538-7445.AM2017-4846
Abstract 4849: ELMO1 promotes metastasis in colorectal cancer cells via activation of MAPK/ERK signaling pathway
Authors: Zheng Xiao-bin , Zhou Chi , Cheng Hai-chun , Hu Tuo , Liu Hua-shan , Liu Xuan-hui , Wu Xian-rui , Wang Feng-wei , Chen Yu-feng , Wang Jian-ping , He Xiao-sheng , Lan Ping 
Published: July 2017

Abstract
Background and Aim: Engulfment and cell motility 1 (ELMO1) has been linked to the invasive phenotype of various types of cancer cells such as glioma cells, rhabdomyosarcoma cells, ovarian cancer cells and so on. However, the biological functions of ELMO1 in colorectal cancer (CRC) cells remains unclear. The aim of this study is to evaluate the role of ELMO1 in the metastasis in CRC.
Methods: The expression level of ELMO1 was detected using quantitative RT-PCR and western blot in 9 CRC cell lines and 1 human colon epithelial cell line NCM460. ELMO1 was overexpressed via lentiviral vector system and silenced using specific small interference RNA (si-ELMO1) in HCT116 and SW620. Then wound-healing, migration assay and invasion assay were carried out to investigate the function of ELMO1 in CRC cells. Western blot was performed to detect the change of signaling molecule extracellular signal-regulated kinase 1/2 (ERK1/2) following the down-regulated or up-regulated expression of ELMO1.
Results: ELMO1 expression was inhibited by si-ELMO1 and was overexpressed by ELMO1-cDNA in HCT116 and SW620. Ectopic expression of ELMO1 in HCT116 and SW620 was shown to promote migration and invasion, while inhibited ELMO1 expression suppressed the capacity of cell migration and invasion. Furthermore, ELMO1 induced migration and invasion in CRC cells was found to be associated with the activation of MAPK/ERK pathway.
Conclusions: High expression of ELMO1 was found to be associated with the metastasis via the activation of MAPK/ERK signaling pathway. This finding provides a molecular basis for the role of ELMO1 in the progression of CRC, which may suggest a novel target for the treatment of CRC.
Citation Format: Xiao-bin Zheng, Chi Zhou, Hai-chun Cheng, Tuo Hu, Hua-shan Liu, Xuan-hui Liu, Xian-rui Wu, Feng-wei Wang, Yu-feng Chen, Jian-ping Wang, Xiao-sheng He, Ping Lan. ELMO1 promotes metastasis in colorectal cancer cells via activation of MAPK/ERK signaling pathway [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 4849. doi:10.1158/1538-7445.AM2017-4849
Abstract 485: Epigentic silencing of miR-142-3p promotes metastasis by targeting ZEB2 in NPC
Authors: Li Yingqin , Liu Na , Ma Jun 
Published: July 2017

Abstract
Metastasis is the major cause of cancer-related death in nasopharyngeal carcinoma (NPC). However, the molecular mechanisms governing metastasis remain poorly understood in NPC. Here, we demonstrated that miR-142-3p was downregulated and significantly suppressed NPC cell migration, invasion in vitro and in vivo. We identified zinc finger E-box binding homeobox 2 (ZEB2) as a direct target of miR-142-3p, and its overexpression rescued the inhibitory effects of miR-142-3p in NPC. Importantly, miR-142-3p downregulation was associated with DNA methylation within the miR-142 locus. Enhancer of zeste homologue 2 (EZH2) suppressed miR-142 methylation and miR-142-3p expression. Systemic reversal of miR-142 silencing suppressed lung metastasis of NPC cells. Furthermore, miR-142 hypermethylation was associated with poor metastasis-free survival. This study demonstrates a suppressive role of miR-142-3p in metastasis and uncovers an epigenetic mechanism for miR-142-3p silencing in NPC, suggesting a potential prognostic factor and therapeutic target to combat metastasis in NPC.
Note: This abstract was not presented at the meeting.
Citation Format: Yingqin Li, Na Liu, Jun Ma. Epigentic silencing of miR-142-3p promotes metastasis by targeting ZEB2 in NPC [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 485. doi:10.1158/1538-7445.AM2017-485
Abstract 4862: SORBS1-AHNAK complex regulates metastatic properties of cancer
Authors: Cho Woo-Cheol , Jang Ji-Eun , Ku Ja-Lok 
Published: July 2017

Abstract
Purpose: CAP encoded by SORBS1, Vinexin and ArgBP2 is participated in the SoHo family of proteins. The SoHo protein interacts with different signaling molecules and involves with cell migration, and has been implicated in a variety of cellular processes including insulin-stimulated glucose transport. CAP has specific role in the stabilization of adhesion complexes and the consequent effect of cell migration. It is possible that CAP or complex between CAP and other proteins induces change of cancer cell characters. We assumed that SORBS1 has substantial role of cell proliferation, migration and interaction with other subcellular proteins.
Methods and materials: To elucidate endogenous role of SORBS1, colorectal cancer cell lines were manipulated by pcDNA, siRNA and shRNA in some colorectal cancer cell lines. Function of SORBS1 as regulator of cancer proliferation was demonstrated by cell cycle assay. And several methods including western blotting, cell migration assay and immunoprecipitation assay were performed for determining role of SORBS1 related other metastatic properties.
Conclusion: Colony formation ability and proliferation were induced by SORBS1-overexpression in HT29 cell line. In contrast, transient suppression of SORBS1 inhibits cell proliferation. Moreover, when SORBS1 was constantly suppressed in HCT-116 and SNU-C4 cell line, cell migration was impeded. According to immunoprecipitation data, we chose the AHNAK protein as the convincing candidate protein related with SORBS1. An interaction of SORBS1 and AHNAK was observed in both cytoplasm and nucleus. Expression level of SORBS1 and AHNAK was also negative correlation in extraction of cytoplasm and nucleus.
SORBS1 and AHNAK bind each other as form of protein complex, however, AHNAK known as nucleoprotein is abundant in both cytoplasm and nucleus when SORBS1 is suppressed. Consequently, these results indicate that SORBS1 has a key role of cancer cell growth and invasiveness through regulation of AHNAK expression and degradation.
Note: This abstract was not presented at the meeting.
Citation Format: Woo-Cheol Cho, Ji-Eun Jang, Ja-Lok Ku. SORBS1-AHNAK complex regulates metastatic properties of cancer [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 4862. doi:10.1158/1538-7445.AM2017-4862
Abstract 4879: Genomic and epigenomic profiling of high-stage neuroblastoma
Authors: Ohira Miki , Tatsumi Yasutoshi , Nakamura Yohko , Tatsuno Kenji , Tsutsumi Shuichi , Yamamoto Shogo , Nagae Genta , Renard-Guillet Claire , Sugino Ryuichi , Nagase Hiroki , Kamijo Takehiko , Aburatani Hiroyuki , Nakagawara Akira 
Published: July 2017

Abstract
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor with a wide range of clinical phenotypes from spontaneous regression to highly resistant to chemotherapy. Despite intense multi-modal therapy, NB remains the second most common cause of cancer deaths among children. MYCN amplification is the most prominent poor prognosis factor for NB, however, certain subgroup of high stage tumor without MYCN amplification also shows low survival rate in terms of long-term follow-up (10 years survival rate was 51%, n=161). To elucidate the molecular basis of malignant subtype of NB, integrated genomic and epigenomic analyses were performed. Array CGH of 537 tumors indicated that genomic subgroups of 17q gain, with 1p loss and/or 11q loss, exhibited aggressive characteristics even without MYCN amplification. Whole exome sequencing of 92 high stage, MYCN-non-amplified primary tumors (SureSelect XT Human All Exon V4, mean depth CDS:138, x20 coverage:96%) identified 1,735 non-silent somatic mutations, among which 53 were significant mutations observed more than once in the sample set. Aggressive tumors (died of disease, n=48) had several notable features, with mutations in chromatin remodeling/modulating genes (27%, cf. ATRX), in DNA-damage response (30%), in TP53 (28%) and RB (22%)-related gene networks, as well as with high TERT expression (38%). By hierarchical clustering of methylome signature (Infinium HumanMethylation450 BeadChip), the 92 tumors were subdivided into four clusters. Unfavorable cluster-2 and -4 exhibited hyper-methylation phenotypes in CpG islands and the former was enriched by MYCN-amplified tumors. These two clusters (53%) showed strong correlation with patient prognosis (p=0.0055). 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 NBs.
Citation Format: Miki Ohira, Yasutoshi Tatsumi, Yohko Nakamura, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Genta Nagae, Claire Renard-Guillet, Ryuichi Sugino, Hiroki Nagase, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara. Genomic and epigenomic profiling of high-stage neuroblastoma [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 4879. doi:10.1158/1538-7445.AM2017-4879
Abstract 4889: Characterizing the viromes in pediatric cancers through whole genome sequencing
Authors: Chang Ti-Cheng , Easton John , Pinto Emilia M. , Zhang Jinghui , Wu Gang 
Published: July 2017

Abstract
Viral infections have been associated with the development of adult cancers such as cervical carcinomas and head/neck cancers. However, there is lack of clear understanding of the composition of virome in pediatric cancers. Here, we made the first attempt to identify differentially enriched viral communities in biological material from pediatric cancer patients, and to predict virus integration sites that may be associated with etiology or tumor progression of pediatric cancers.
The Pediatric Cancer Genome project (PCGP) has previously generated whole-genome sequencing (WGS) data of matched cancer-normal samples for over 600 pediatric patients from three classes of cancers: leukemia, solid tumors, and central nervous system (CNS) cancers. We re-constructed the virome composition profiles in each sample based on the unmapped and partially mapped Illumina reads extracted from the PCGP WGS data. Taxonomic assignments of the extracted read data were conducted using the Kraken metagenomic pipeline and virus integration sites were predicted by the VyPER pipeline. Custom scripts were used for downstream comparative analyses.
A comparison of the alpha diversity of each virome indicated that the tumor samples in general have a lower diversity compared to the normal samples across all tumor types. This trend holds true in leukemia, where both tumor and normal samples were blood derived, suggesting that this is not due to different origins of the tumor samples.
Ordination analyses based on the viral composition identified distinct clusters in the three classes of cancers. These clusters were formed mainly by samples of medulloblastoma for CNS, T-ALL and hypodiploid B-ALL for leukemia, retinoblastoma and rhabdomyosarcoma for solid tumors. Viruses, such as phages, herpesviraidae and several sarcoma viruses, were differentially enriched in these clusters.
Potential integration with retroviruses or herpesviruses was predicted at a high frequency. Less frequent integration events were also detected with known oncogenic viruses, such as simian virus 40 and human adenovirus C, which were under deep sequencing validation.
In summary, our comprehensive characterization of the virome in a wide spectrum of pediatric cancers revealed a potential connection between specific viral communities and integration sites in certain distinct types of pediatric cancers. Our findings highlight a possible mechanism underlying the tumor progression in pediatric patients.
Citation Format: Ti-Cheng Chang, John Easton, Emilia M. Pinto, Jinghui Zhang, Gang Wu. Characterizing the viromes in pediatric cancers through whole genome sequencing [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 4889. doi:10.1158/1538-7445.AM2017-4889
Abstract 4892: MOSPD2, a newly characterized protein, promotes breast cancer metastasis
Authors: Mendel Itzhak , Salem Yaniv , Yacov Niva , Propheta-Meiran Oshrat , Breitbart Eyal 
Published: July 2017

Abstract
Introduction: We have previously described motile sperm domain-containing protein 2 (MOSPD2), a protein which up until recently no function was ascribed to, as a key regulator of monocyte migration in-vitro. In this study, the role of MOSPD2 in promoting breast cancer migration and metastasis in-vitro and in-vivo was assessed.
Experimental procedure: The prevalence of MOSPD2 was evaluated by IHC in tissue microarray layered with cores, representing different stages of invasiveness in breast cancer. MOSPD2 abundance was scored according to the staining intensity on a scale from 0 to 3. MOSPD2 expression was silenced in MDA-231 breast cancer cell line using lentiviral particles for sh-RNA or CRISPR-CAS9 (CRISPR). Cells were then tested by a trans-well assay for migration towards EGF in vitro as well as for lung dissemination following orthotopic or systemic inoculation in vivo. For mechanism studies, EGF-induced signaling events were analyzed.
Results: Within normal adjacent tissue (NAT), 82% of the samples had no staining and the remaining 18% percent displayed an intensity of 1. In the tissue cores with in-situ carcinoma pathology, 79% of the samples had no staining intensity while the remaining 21% only scored 1 or 2. However, analysis of invasive and metastatic cancer demonstrated higher frequency in score of 2 and increased staining intensity up to score of 3 compared with NAT and in-situ carcinoma. Thus, the percent of combined scores 2 and 3 for invasive lobular carcinoma, invasive ductal carcinoma and metastatic invasive ductal carcinoma were 63%, 77% and 81%, respectively. MOSPD2-silenced cells, either by sh-RNA or by CRISPR, were severely impaired in their ability to migrate in-vitro towards EGF. Following EGF activation of CRISPR-Control MDA-231 cells, all tested proteins down-stream to the EGFR pathway, including AKT and p38, became phosphorylated. However, in CRISPR-MOSPD2 silenced cells, phosphorylation of all tested proteins excluding p38 were markedly inhibited. Moreover, activation with IGF of CRISPR-MOSPD2 MDA-231 cells did not hinder AKT phosphorylation. In vivo, SCID mice injected orthotopically or systemically with CRISPR-MOSPD2 silenced MDA-231 cells displayed significantly reduced number of metastases in the lungs relatively to mice injected with CRISPR-Control treated cells.
Conclusions: We suggest that MOSPD2 promotes metastasis of breast cancer cells and is a potential target for the treatment of metastatic breast cancer.
Citation Format: Itzhak Mendel, Yaniv Salem, Niva Yacov, Oshrat Propheta-Meiran, Eyal Breitbart. MOSPD2, a newly characterized protein, promotes breast cancer metastasis [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 4892. doi:10.1158/1538-7445.AM2017-4892