bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 103: Expression and regulation of MMP9 and RECK in human oral squamous cell carcinoma progression and invasion
Authors: Pramanik Kamdeo Kumar , Rana Basabi , Rana Ajay , Mishra Rajakishore 
Published: August 2018

Abstract
Purpose: Matrix metalloproteinase-9 (MMP-9), a Zn-dependent endopeptidase is known to play a central role in oral cancer pathogenesis. Recently we observed differential function of MMP-9 and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) respectively in OSCC invasion. We hypothesize that the downregulation of MMP-9 via RECK promotes human oral cancer progression and invasion.
Experimental procedure: The mRNA expression, protein expression and activity of MMP-9/2, expression of transcription factors like Snail, c-Myc, β-catenin and protein-protein interaction of TIMP1/RECK with MMP9 and promoter methylation of RECK gene were assessed by using RT-PCR, immunohistochemistry (IHC), Western blotting, co-immunoprecipitation, gelatin zymography, and bisulphate modification-PCR analyses. Wnt5a and LPA mediated MMP-9 regulation as well as the MMP-9 regulation by the exogenously expression of RECK, GSK3β (WT) or non phosphoryable active GSK3β (S9A) was also performed in oral tongue SCC derived SCC-9 cells.
Summary: We observed up-regulation/activation of MMP-9 was associated with decreased expression of RECK and progression and invasion of OSCC. MMP-9 expression/ activity was positively correlated with inactivation of GSK3β signaling. Conversely, a link between inactivation of GSK3 signaling and the progressive silencing of RECK gene through promoter hypermethylation was observed. Finally, Wnt5a and LPA mediated increased MMP-9 and decreased RECK expressions were observed.
Conclusion: Taken together, these results demonstrated the influence of a novel signaling axis GSK3β-RECK-MMP-9 to drive OSCC progression and invasion. Thus, targeting this pathway may be exploited for treating OSCC.
Citation Format: Kamdeo Kumar Pramanik, Basabi Rana, Ajay Rana, Rajakishore Mishra. Expression and regulation of MMP9 and RECK in human oral squamous cell carcinoma progression and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 103.
Abstract 1034: Genotyping of patient-derived xenograft tumors using short tandem repeats: Challenges and observations in ensuring concordance across passages for effective preclinical studies
Authors: Sisson Bridgette , Hesse Andrew , Soucy Melissa , Bergeron Daniel , Burns Shelbi , Kelly Kevin , Jocoy Emily , Bundy Margaret , Reddi Honey V. 
Published: August 2018

Abstract
Patient derived xenograft (PDX) tumor models represent the closest step to in-human trials for cancer drug research and are therefore an invaluable resource. Implantation of a cancerous tissue from a patient's primary tumor directly into an immune-deficient mouse, generating a xenograft tumor potentially mimics the tumor microenvironment in the patient and allows for the evaluation of therapies specific to a particular tumor. One of the significant challenges associated with PDX tumors is the potential loss of the human component or the take-over by mouse tissue with every passage into a new mouse model. Short tandem repeats (STRs) are short intronic sequences of DNA that are highly polymorphic and contain a pattern of nucleotides repeated in tandem. STRs can be found in distinct regions of both prokaryotes and eukaryotes organisms, with each organism containing a unique combination of the STR allelic frequencies that allow for individuals to be unambiguously identified. STR analysis is routinely used to genotype PDX tumors comparative to the original resected human cancerous tissue, ensuring concordance with original tissue and to identify mouse tissue contamination with progressive passages. The Jackson Laboratory for Genomic Medicine's CLIA laboratory has evaluated over 170 PDX tumor samples from multiple mouse model passages across 105 diverse PDX mouse models. Of those samples analyzed, genomic DNA for 33 had been extracted from fresh frozen tissue and for 143 extracted from Formalin Fixed Paraffin embedded tissue (FFPE). The current study presents the challenges and discrepancies observed in our evaluation relative to number of passages for each tumor, sample type (FFPE vs fresh frozen) - reflective of tumor heterogeneity and also potential encroachment by mouse tissue. We also present results of a cross institutional comparative STR analysis study in 123 samples wherein discordance observed in certain cases were a result of differing sample types, suggestive that tumor heterogeneity can affect the STR results and could be a leading cause for cross institutional discordant genotyping results.
Citation Format: Bridgette Sisson, Andrew Hesse, Melissa Soucy, Daniel Bergeron, Shelbi Burns, Kevin Kelly, Emily Jocoy, Margaret Bundy, Honey V. Reddi. Genotyping of patient-derived xenograft tumors using short tandem repeats: Challenges and observations in ensuring concordance across passages for effective preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1034.
Abstract 1044: Establishment and characterization of rare breast patient-derived xenograft models as a potential resource for personalized medicine
Authors: Kuasne Hellen , Savage Paul , Ramirez Constanza Martinez , Liu Leah , Muñoz-Ramos Valentina , Pilon Virginie , Monast Anie , Johnson Radia , Bertos Nicholas , Asselah Jamil , Bouganim Nathaniel , Petrecca Kevin , Meterissian Sarkis , Omeroglu Atilla , Basik Mark , Park Morag 
Published: August 2018

Abstract
Breast cancer (BC) exhibits a wide range of morphologic phenotypes and gene expression profiles. Most of the studies that led to the identification of intrinsic molecular subtypes in BC were limited to invasive ductal carcinomas of the breast and did not take rare histopathologic subtypes into account. Rare histopathologic BC subtypes (collectively less than 2% of all breast cancer) have particular prognostic and clinical characteristics. There is no current established treatment that takes into account the specificity of rare BC subtypes. This is mainly due to the absence of clinical trials to determine the optimal management of these rare pathologies. The establishment of relevant preclinical models and molecular characterization of rare BC subtypes is essential for identifying directed and suitable therapeutic regimens for BC patients diagnosed with these rare histopathologic variants. Patient-derived xenograft (PDX) has been recognized as a valuable method to evaluate the clinical diversity of breast cancer. These models were shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, and personalized medicine strategies. We developed a cohort of eight BC rare histopathologic subtypes, including four metaplastic, one adenoid cystic, one IDC pleomorphic, one neuroendocrine, and one mucinous BC subtype. These PDXs and their primary tumors were submitted to whole-genome sequencing (WGS) and RNA sequencing. We also evaluated a total of 255 proteins by reverse phase protein array (RPPA) in these PDX samples. We are currently performing conditional reprogramming experiments to generate cell lines from these rare BC PDXs. Our preliminary results indicate that pathways related to PI3K/AKT, ERK/MAPK, mTOR, HGF, ERBB, AMPK and IL3 signaling are disrupted in rare BC subtypes. Several genes belonging to these pathways are dysregulated in rare BC tumors, and therefore represent potential therapeutic targets for personalized treatment.
Citation Format: Hellen Kuasne, Paul Savage, Constanza Martinez Ramirez, Leah Liu, Valentina Muñoz-Ramos, Virginie Pilon, Anie Monast, Radia Johnson, Nicholas Bertos, Jamil Asselah, Nathaniel Bouganim, Kevin Petrecca, Sarkis Meterissian, Atilla Omeroglu, Mark Basik, Morag Park. Establishment and characterization of rare breast patient-derived xenograft models as a potential resource for personalized medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1044.
Abstract 1053: Highly characterized patient-derived PDX breast cancer collection for preclinical efficacy studies
Authors: Melton Michele 
Published: August 2018

Abstract
We have acquired a world-class collection of highly characterized patient-derived breast cancer models (PDX) from Washington University, St. Louis, MO (1). We have established growth curves for 17 of these lines, 6 ER+, 2 HER2+ and 4 triple-negative (TNBC) models beyond what was originally published. Continued characterization of these models is ongoing in our lab to ensure the integrity of the models is being maintained over multiple rounds of propagation. Short tandem repeat (STR) analysis, sequencing, quantitative RTPCR and Western blots were run to confirm genotypic and phenotypic fidelity of many of these model. To further characterize these models, RNA samples have been run using NanoString PanCancer gene expression analysis with 770 genes from 13 cancer-associated pathways including: MAPK, STAT, PI3K, RAS, Cell Cycle, Apoptosis, Hedgehog, Wnt, DNA Damage Control, transcription regulation, chromatin modification and TGF-β. Results: These data sets show that we have maintained the integrity of the WHIM PDX models over several passages in mice and provided confidence in the use of these models for preclinical efficacy studies.
Reference: 1. Li et al., Cell Reports 2013;4:1116-30.
Citation Format: Michele Melton. Highly characterized patient-derived PDX breast cancer collection for preclinical efficacy studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1053.
Abstract 1055: Lymphotoxin-alpha plays key roles in lymphoproliferative lesions arising in patient-derived cancer xenografts
Authors: Chijiwa Tsuyoshi , Komura Daisuke , Haraguchi Mizuha , Hashimoto Haruo , Suemizu Hiroshi , Katayama Makoto , Nakamura Yoshiyasu , Furukawa Daisuke , Isagawa Takayuki , Katoh Hiroto , Moriya Takashi , Ishikawa Shumpei , Miyagi Yohei , Nakamura Masato 
Published: August 2018

Abstract
Patient-derived xenograft (PDX) mouse models from engrafting fresh surgical specimens directly onto immunodeficient mice have enabled the development of more relevant in vivo models for human cancers. PDX models retain similar morphology, heterogeneities, and molecular signatures with the original cancers. Moreover, PDXs with clinical information, termed “cancer xenopatients”, are remarkable systems in personalized medicine for cancer. During the establishment process, a transplantable lymphoproliferative lesion (LPL) that replaces the original tumor cells sometimes occurs in severely immunodeficient mice. Although the occurrence of LPL is the most problematic aspect of the establishment of PDX, its mechanisms are unknown. We previously reported that the LPL phenomenon resembled the graft-versus-host disease (GVHD)-like mechanism and was suppressed by anti-GVHD agents. In the present study, we genomically analyzed the detailed mechanism of LPL in PDX mouse models. In our previous study, we established three LPL-PDX/NOG lines. These LPL-PDX lines were re-transplanted onto NOG mice and the xenograft tumors were then harvested for study. Genome sequencing and comprehensive analyses of tumor-stroma interactions (CAncer-STromal INteractome analysis, CASTIN) were performed on mRNA of these LPL-PDX/NOGs. Immunohistochemistry demonstrated that LPL tissues consisted of B-cells, T-cells, and differentiated plasma cells. CASTIN revealed tumor-stroma interactions in PDX/NOG comprehensively and quantitatively at the gene expression level by distinguishing gene arrangements in human tissue (cancer or LPL) from mouse tissue (stroma) by signal strength and dependency. Some strong interactions were found for these LPL-PDX/NOGs; VEGFB-FLT1, LTA-LTBR, LTA-TNFRSF1A, IL13-IL4R, IL13-IL13RA1, and SEMA4F-NRP2. Suppression of LPL-PDX/NOG by the anti-GVHD agent FK506 (1.0 mg/kg/day, 4 weeks) decreased interactions of LTA-LTBR and LTA-TNFRSF1A. Based on these results, LPLs during establishment of PDX occur due to a lymphotoxin-alpha-related mechanism. Controlling lymphotoxin-alpha related interactions may improve the establishment rate of PDX in severely immunodeficient mice.
Citation Format: Tsuyoshi Chijiwa, Daisuke Komura, Mizuha Haraguchi, Haruo Hashimoto, Hiroshi Suemizu, Makoto Katayama, Yoshiyasu Nakamura, Daisuke Furukawa, Takayuki Isagawa, Hiroto Katoh, Takashi Moriya, Shumpei Ishikawa, Yohei Miyagi, Masato Nakamura. Lymphotoxin-alpha plays key roles in lymphoproliferative lesions arising in patient-derived cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1055.
Abstract 1060: Longitudinal profiling of plasma derived extracellular vesicles (EVs) from women presenting with metastatic triple-negative breast cancer (mTNBC) informs on metastatic location and treatment outcome
Authors: Lindsay Sinéad , McIntyre Jennifer , Gubbins Luke , Smith Martina , Kerr Laura , Kavanagh Emma , Higgins Michaela J. , Hennelly Bryan , Dowling Paul , Byrne Hugh , McCann Amanda 
Published: August 2018

Abstract
Background: Women presenting with Triple Negative Breast Cancer (TNBC) have an increased risk of recurring at distant visceral metastatic sites such as brain, lungs and liver rather than bone compared to oestrogen-receptor-positive breast cancer. (Rakha et al., 2011, Wood 2004). The preferential homing of TNBC cancer cells to these sites is not clearly understood, but is increasingly being attributed to the ability of extracellular vesicles (EVs) released by chemoresistant cancer cells to circulate to distant sites creating metastatic niches and paving the way for organ-specific metastases.
Hypothesis: We hypothesise that the physical EV properties, macromolecular and proteomic content of these EVs could potentially determine the risk of metastasis and align with these “preferred” metastatic locations.
Methodology: This project uses nanoparticle tracking analysis (NTA), infra-red and mass spectroscopy to generate unique patient-specific EV longitudinal signatures of women diagnosed with organ defined metastatic TNBC. These signatures hold potential as “unique identifiers” of clinically documented organ-specific metastases. All profiles generated are compared longitudinally to the patient's initial baseline sample and also to age matched female control plasma samples.
Results and Conclusions: Preliminary results have developed SOPs to (i) successfully enrich for EVs from patient plasma samples and (ii) employ nanoparticle tracking analysis, infra-red and mass spectroscopic profiling to develop unique longitudinal patient specific EV signatures. The longitudinal profiling of EV signatures from patients with metastatic TNBC will potentially (a) predict response to therapy, (b) uniquely identify risk of and potential location of metastatic site/sites and (c) inform on patient outcome. Following this multidisciplinary profiling of our mTNBC, our remit is to recapitulate this profiling into the primary TNBC setting to identify potential sites of organ specific metastases ahead of any detection on an x-ray or scan, thereby informing on clinical management.
Citation Format: Sinéad Lindsay, Jennifer McIntyre, Luke Gubbins, Martina Smith, Laura Kerr, Emma Kavanagh, Michaela J. Higgins, Bryan Hennelly, Paul Dowling, Hugh Byrne, Amanda McCann. Longitudinal profiling of plasma derived extracellular vesicles (EVs) from women presenting with metastatic triple-negative breast cancer (mTNBC) informs on metastatic location and treatment outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1060.
Abstract 1061: Advanced quantitative mass-spectrometry-based SILAC proteome profiling of Y-box binding protein-1 (YB-1) overexpressing breast cancer cells unravels proteins involved in metastasis
Authors: Lim Jia Pei , Nair Sunitha , Shyamasundar Sukanya , Gunaratne Jayantha , Bay Boon Huat 
Published: August 2018

Abstract
Metastasis is responsible for the majority of cancer related deaths and remains a global medical challenge in cancer treatment. The Y-box binding protein-1 (YB-1), a DNA and RNA binding protein, is known to regulate a plethora of fundamental cellular processes, including cell proliferation, chemoresistance and DNA repair. There is also cumulative evidence that YB-1 enhances breast cancer spread although the exact mechanism of YB-1-mediated metastasis is still not clear. Hence, we aim to determine the role of YB-1 overexpression in breast cancer progression. We first stably overexpressed YB-1 in non-aggressive MCF7 breast cancer cells (MCF7-YB-1) using a turboGFP tagged plasmid and performed phenotypic assays. We observed a significant increase in cell migration in MCF7-YB-1 in the Boyden chamber migration assay, which was substantiated by performing live imaging of the cells in a wound healing assay. Furthermore, a significant decrease in cell proliferation with G1 phase arrest was observed by the alamarBlue assay and flow cytometry analysis of propidium iodide staining, respectively for MCF7-YB-1 cells. We then performed a whole proteome analysis by stable isotope labelling with amino acids in cell culture (SILAC), a powerful proteomics platform. The whole proteome analysis identified 122 upregulated proteins and 120 downregulated proteins in the MCF-7-YB-1 cells. Bioinformatics analysis of the differentially regulated proteins using the Metacore software revealed the involvement of proteins that promote cell migration and invasion, such as those belonging to the S100 family which are enriched in the extracellular vesicles and exosome compartment, providing some mechanistic insights into the metastasis promoting role of YB-1. Taken together, our results showed that YB-1 could enhance the migratory potential of breast cancer cells, an important step in the metastatic cascade and therefore warrants a more in-depth study.
Acknowledgement: Jia Pei Lim is a recipient of Ong Hin Tiang Scholarship in Cancer Research. This research was supported by Ministry of Education Grant (MOE2013-T2-1-129).
Citation Format: Jia Pei Lim, Sunitha Nair, Sukanya Shyamasundar, Jayantha Gunaratne, Boon Huat Bay. Advanced quantitative mass-spectrometry-based SILAC proteome profiling of Y-box binding protein-1 (YB-1) overexpressing breast cancer cells unravels proteins involved in metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1061.
Abstract 1074: Expression of p39 and Rb in lung cancer and its correlation with clinicopathologic parameters
Authors: Perez-Morales Jaileene , Rivera Stephanie , Torres Bryan , Rodriguez Xavier , Isidro Angel , Santiago-Cardona Pedro 
Published: August 2018

Abstract
Lung cancer is characterized by its aggressiveness and proclivity for early metastasis. A predictor of metastasis of NSCLC rely on post-resection evaluation of tumor histology, which is a severe limitation since only 15% of the patients are diagnosed with resectable disease. Hence, there is a need to characterize biomarkers with metastasis-predicting value in pre-resection small biopsy specimens. Rb is a tumor suppressor inactivated due to hyper-phosphorylation in NSCLC. Our preliminary data relates the Rb S249 phosphorylation to an epithelial-to-mesenchymal transition (EMT), a trait strongly associated to metastasis and increase in CDK5 activator p39. Here, we examined the prognostic significance of Rb S249 and p39 as biomarkers of metastasis staging in non-small cell lung cancer. Our hypothesis is that Rb hyper-phosphorylation in S249 can have prognostic value by being associated with a metastatic phenotype and EMT. To determine p39 and Rb phosphorylation in lung cancer, immunohistochemistry analysis was performed on two lung cancer microarrays. Three pathologists observed the microarrays and scored them using the all-red scoring system. P39 and Rb phosphorylation in S249 were more present in lung tumors than adjacent normal tissue. P39 positive expression had a positive correlation with staging, lymph node involvement, and metastasis. Rb phosphorylation in residue S249 had a positive correlation with histological grading. Using general linear model, we determined that staging can be predicted when combining phosphorylation of Rb S249 and p39. Our analysis suggests that p39 and Rb S249 are likely to be diagnostic biomarkers for lung cancer metastasis.
Citation Format: Jaileene Perez-Morales, Stephanie Rivera, Bryan Torres, Xavier Rodriguez, Angel Isidro, Pedro Santiago-Cardona. Expression of p39 and Rb in lung cancer and its correlation with clinicopathologic parameters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1074.
Abstract 1084: TRAF4-mediated NGF receptor TrkA ubiquitination regulates prostate cancer metastasis
Authors: Singh Ramesh , Karri Dileep , Shao Jiangyong , Dasgupta Subhamoy , Huang Shixia , Edwards Dean P. , O'Malley Bert W. , Yi Ping 
Published: August 2018

Abstract
Receptor tyrosine kinases (RTKs) are important drivers of cancers. In addition to genomic alterations, aberrant activation of wild type RTKs play an important role in driving cancer progression. However, the underlying mechanisms of how RTKs drive prostate cancer remains incompletely characterized. Here we show that non-proteolytic ubiquitination of RTK regulates its kinase activity and contributes to RTK-mediated prostate cancer metastasis. TRAF4, a RING domain E3 ubiquitin ligase, is highly expressed in metastatic prostate cancer. We demonstrated here that it is a key player in regulating RTK mediated prostate cancer metastasis. We further identified TrkA, a neurotrophin receptor tyrosine kinase, as a TRAF4-targeted ubiquitination substrate that promotes cancer cell invasion and genetic ablation of TrkA abolished TRAF4-dependent cell invasion. TRAF4 promoted atypical K27 and K29-linked ubiquitination at the TrkA kinase domain and increased its kinase activity. Mutation of TRAF4-targeted ubiquitination sites abolished TrkA tyrosine auto-phosphorylation and its interaction with downstream effector proteins. TRAF4 knockdown also suppressed nerve growth factor-stimulated TrkA downstream p38 MAPK activation and subsequent invasion-associated gene expression. Furthermore, elevated TRAF4 levels significantly correlated with increased NGF-stimulated invasion-associated gene expression in prostate cancer patients, indicating this signaling axis is significantly activated during oncogenesis. Our results revealed a post-translational modification mechanism contributing to aberrant non-mutated receptor tyrosine kinase activation in cancer cells.
Citation Format: Ramesh Singh, Dileep Karri, Jiangyong Shao, Subhamoy Dasgupta, Shixia Huang, Dean P. Edwards, Bert W. O'Malley, Ping Yi. TRAF4-mediated NGF receptor TrkA ubiquitination regulates prostate cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1084.