bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2847: Human CYP1B1 induces cancer cell metastasis through Sp1-mediated activation of uPA-uPAR signaling pathway
Authors: Kwon Yeo-Jung , Shin Sangyun , Chun Young-Jin 
Published: July 2021

Abstract
Human CYP1B1 is known as a major metabolizer for estrogen and shows tumor-specific hyper-expression. To explore the role of CYP1B1 on metastasis of human cancer cells, we studied the effects of CYP1B1 inhibition and activation in MCF-10A, MCF-7, MDA-MB-231, and HeLa cells. CYP1B1 significantly induced expression of urokinase-type plasminogen activator receptor (uPAR) as well as uPA. Treatment with DMBA, a well-known CYP1B1 inducer, enhanced uPAR expression while CYP1B1 siRNA and TMS (tetramethoxystilbene), a specific CYP1B1 inhibitor, suppressed uPAR. We also found that CYP1B1 activated uPAR signaling through regulation of related factors including integrin β1 and α5. Interestingly, uPAR overexpression only caused a significant increase of integrin β1 and α5 in protein levels, indicating protein degradation may play an important role in regulating integrin protein level. Surprisingly, CYP1B1 down-regulated p53 expression through MDM2 activation and nutlin-3a, an inhibitor for MDM2, blocked the promoting effects of DMBA on uPAR, which explains that CYP1B1 induced uPAR expression through regulation of MDM2-p53 system. In addition, we revealed that CYP1B1 regulates uPAR through activation of Sp1 transcription factor. CYP1B1 and its enzymatic product, 4-OHE2, promote Sp1 expression levels in both mRNA and protein levels and subsequently Sp1 elevates the transcriptional activity of uPAR through binding to promoter region of uPAR. Taken together, our data suggest that CYP1B1 promotes cancer cell metastasis via activating uPAR pathway which is one of the targets of p53 and Sp1 signaling.
Citation Format: Yeo-Jung Kwon, Sangyun Shin, Young-Jin Chun. Human CYP1B1 induces cancer cell metastasis through Sp1-mediated activation of uPA-uPAR signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2847.
Abstract 2850: Astrocyte-breast cancer interactions facilitate brain metastasis
Authors: Dangoor Sahar Israeli , Hadad Ori , Satchi-Fainaro Ronit 
Published: July 2021

Abstract
Diagnosis and treatment of breast cancer patients have been considerably improved, including those at the metastatic stage. However, brain metastasis still presents a major clinical challenge, and it is a leading cause of death. Unfortunately, there are no targeted therapies specific for this secondary tumor, and the current treatment modalities present limited clinical outcomes. Thus, better understanding of the pathways involved in the metastatic cascade, which lead to brain metastases colonization and progression, is essential. To that end, we investigated the mutual effects of astrocytes and breast cancer cells, using the traditional 2-dimensional (2D) cell-culture and a newly-established 3-dimensional (3D) model of multicellular breast cancer brain metastases spheroids. We found that astrocytes enhance the proliferation, migration and invasion of breast cancer cells, suggesting a supportive role for astrocytes in the metastatic process of breast cancer in the brain. Using a protein array, we identified several cytokines which were elevated following the co-culturing of breast cancer cells with astrocytes, suggesting them as potential key candidates involved in breast cancer-brain stroma interactions. One of these cytokines was MCP-1, which is a chemokine that is associated with poor prognosis in breast cancer patients. When it was functionally neutralized, breast cancer cell proliferation and migration rates were decreased, in addition to reduced invasion shown in our 3D-spheroid model. Considering these results, MCP-1 is proposed as one of the key factors promoting breast cancer brain metastasis. Although further validation using in vivo models is still required, this study deepens our understanding of the contribution of the metastatic breast cancer cells-brain microenvironment crosstalk to brain colonization. Taken together, our findings may be utilized to provide a novel therapeutic approach for the prevention of breast cancer brain metastasis following resection of the primary lesion.
Keywords: Breast Cancer, Brain Metastasis, Brain Microenvironment, Astrocytes, Cytokines, Chemokines, MCP-1, CCL2, 3D Tumor Spheroids.
Citation Format: Sahar Israeli Dangoor, Ori Hadad, Ronit Satchi-Fainaro. Astrocyte-breast cancer interactions facilitate brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2850.
Abstract 2853: Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis
Authors: Simó-Riudalbas Laia , Planet Evarist , Offner Sandra , Duc Julien , Abrami Laurence , Dind Sagane , Coudray Alexandre , Coto-Llerena Mairene , Piscuoglio Salvatore , Andersen Claus L. , Bramsen Jesper Bertram , Trono Didier 
Published: July 2021

Abstract
The human genome contains some 4 million transposable element (TE)-derived sequences, which collectively influence gene expression from early embryogenesis to adulthood. The illegitimate production of oncogene-encoding TE-driven transpochimeric gene transcripts (TcGTs) has been noted in tumors, but their participation in the oncogenic process has seldom been demonstrated. Here we describe how the aberrant de-repression of a primate-specific LTR66 endogenous retroviral promoter generates a TcGT overexpressing the great-ape-restricted POU5F1B retrogene in ~65% of 286 colorectal cancers (CRC) patients, correlating with more advanced tumor stages and shorter relapse-free and overall survival. We further demonstrate that the POU5F1B protein stimulates the clonogenic and proliferation capacity of human CRC cell lines in vitro, and their tumorigenic and metastatic potential in mouse xenotransplantation models. Although POU5F1B is a retrotransposition-mediated derivative of the POU5F1/OCT4 transcription factor, its product is a predominantly cytoplasmic protein enriched in membranes that associates with mediators of signal transduction, notably the ERBB2 receptor tyrosine kinase and several of its known interactors. POU5F1B overexpression results in activating genes involved in signaling, and conditioned medium of POU5F1B-overexpressing cells enhances the clonogenic potential of CRC cells in trans. As POU5F1B is encoded by an apparently non-essential gene only lowly expressed in normal tissues, and as POU5F1B-containing TcGTs are detected in other tumors besides CRC, it represents an attractive target for the development of cancer therapies.
Citation Format: Laia Simó-Riudalbas, Evarist Planet, Sandra Offner, Julien Duc, Laurence Abrami, Sagane Dind, Alexandre Coudray, Mairene Coto-Llerena, Salvatore Piscuoglio, Claus L. Andersen, Jesper Bertram Bramsen, Didier Trono. Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2853.
Abstract 2858: DEPDC1B functions as an oncogene in promoting melanoma growth and metastasis
Authors: Hu Feng , Fong Ki On , Cheung May Pui Lai , Yang Xintao , Cheung Martin 
Published: July 2021

Abstract
Background: Melanoma is one of the most aggressive skin cancers due to its therapeutic resistance, and high capacity to metastasize as a late manifestation. The limited effectiveness of the current treatment regimen prompts us to identify new druggable targets in governing the systemic spread of melanoma. Despite the oncogenic role of DEPDC1B in different types of cancer, its functional importance in melanoma growth and metastasis are not fully revealed.
Methods: The expression of DEPDC1B mRNA levels between skin cutaneous melanoma patients and normal samples were compared using TCGA database. Surgically procured tumor specimens from melanoma patients were obtained to investigate the protein levels of DEPDC1B expression by immunofluorescence. Melanoma cell lines WM266-4 and SK-MEL-28 were used for loss- and gain-of-function studies of DEPDC1B in AlamarBlue, EdU staining, colony formation and trans-well invasion assays. Subcutaneous and intravenous injection of melanoma cells treated with either DEPDC1B knockdown (KD) or DEPDC1B overexpression into immunodeficient mice were conducted to examine the effects on tumor growth and lung metastasis respectively.
Results: The expression levels of DEPDC1B mRNA in melanoma biopsies were higher than normal samples and were negatively corelated with both overall survival and disease-free survival. Loss-of-function studies showed that DEPDC1B KD reduced the growth rate, proliferation capacity and colony formation ability of melanoma cells. Consistently, DEPDC1B KD cells gave rise to smaller xenograft tumors and fewer number of lung nodules. In contrast, DEPDC1B overexpression promoted melanoma cell proliferation, colony formation and invasion in vitro, and enhanced xenograft tumor growth and lung metastasis.
Conclusion: The results obtained so far indicate that DEPDC1B acts as an oncogene in promoting melanoma cell growth and metastasis, suggesting a potential drug target in melanoma treatment.
Citation Format: Feng Hu, Ki On Fong, May Pui Lai Cheung, Xintao Yang, Martin Cheung. DEPDC1B functions as an oncogene in promoting melanoma growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2858.
Abstract 2868: A cell based phenotypic assay platform for cancer metastasis drug discovery and diagnostics
Authors: Chowdhury Arnab Roy , Chowdhury Debabani Roy , Pandre Manoj , Roy Samrat , Kannan Sundarajan , Ellingboe John W. 
Published: July 2021

Abstract
Metastatic cancers are difficult to treat and are the cause of about 90% of cancer related deaths. Furthermore, predictive diagnostics are not readily available, and lack of good translational assays has impaired drug discovery. Mestastop has developed a platform of cell based functional assays that aims to address these drug discovery and diagnostic gaps. The platform is comprised of a set of 14 cell based phenotypic assays that capture multiple aspects of the complex process of metastasis, including characterization of the plasticity ratios (EMT, MET) and stemness of cells, invasion, intravasation, circulation, extravasation, and survival in secondary tissues (e.g metabolic shift, exosome secretion). Wild type tumor cells (initially a set of colon tumor cell lines) are utilized in the platform. Non-metastatic wild type cells (e.g. HT-29) that have been engineered into metastatic cells are also utilized to further elucidate metastatic processes, thereby creating two baseline data sets for each assay; one for the normal growing tumor and the other for the select metastatic population. Patient derived tumors are now being analyzed in the platform to help build a translational model. Preclinical animal models are being jointly developed with Immunobiome Inc. (South Korea). As the data from all these assays present a multivariate problem, we are developing a machine learning algorithm, METSCANTM, to analyze the results. The platform will be applied to the screening of novel compounds for drug discovery and of approved drugs for repurposing. Analysis of patient derived tumors may allow for the early detection of patients with high metastatic potential. Four colon cancer cell lines and several standard chemotherapy drugs have been used to validate the platform. A group of triple negative breast cancer cell lines is now being tested. Preliminary data for a set of approved, marketed drugs has further validated the potential of the platform for drug discovery and repurposing. The Mestastop proprietary assay platform will empower biopharma in the discovery of novel drug candidates and repurposing of approved drugs for the treatment of metastasis, and the early diagnosis of cancers with high metastatic potential, thereby addressing the unmet need in the area of cancer metastasis.
Citation Format: Arnab Roy Chowdhury, Debabani Roy Chowdhury, Manoj Pandre, Samrat Roy, Sundarajan Kannan, John W. Ellingboe. A cell based phenotypic assay platform for cancer metastasis drug discovery and diagnostics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2868.
Abstract 2876: Adhesion GPCR CD97/ADGRE5 facilitates invasion in patient-derived glioma stem cells and induces changes in EGFR and Sox2 expression
Authors: Slepak Tatiana I. , Eichberg Daniel G. , Pascoini Ana L. , Komotar Ricardo J. , Ivan Michael E. 
Published: July 2021

Abstract
The main obstacles for effective treatment of Glioblastoma (GBM) are high invasiveness and heterogeneity. Each GBM tumor is composed of multiple genetically distinct subpopulations of Glioma Stem Cells (GSCs), exhibiting high cell plasticity affecting their invasive and proliferative properties. Treatment interventions and changes in microenvironment force GSCs to adapt through gene expression that supports therapeutic resistance. Expression level of the surface receptor CD97/ADRGE5 positively correlates with poor GBM patient prognosis, but its role in this tumor has not been elucidated. Here, we examined the function of CD97 in primary GSCs derived from five GBM tumors, which belong to three major genetic subtypes. We manipulated CD97 levels in these GSCs by knockdown and overexpression and analyzed the following: (i) expression of stem and subtype markers, (ii) in vitro invasive properties, (iii) cell proliferation, (iv) expression of the key proteins that regulate GSCs cellular state and influence their adaptive behavior. Our data showed that CD97 knockdown in GSCs of mesenchymal and classical subtype reduced their invasion rate in vitro. CD97 signaling positively affected expression of Epidermal Growth Factor Receptor, the main driver of astrocyte-like fate in GSCs and changed the expression of the astrocytic marker GFAP. Finally, we discovered a possible link between CD97 and expression of transcription factor Sox2, the key regulator of the endothelial-to-mesenchymal transition process that plays a crucial role in initiation of cancer cell invasion.
Citation Format: Tatiana I. Slepak, Daniel G. Eichberg, Ana L. Pascoini, Ricardo J. Komotar, Michael E. Ivan. Adhesion GPCR CD97/ADGRE5 facilitates invasion in patient-derived glioma stem cells and induces changes in EGFR and Sox2 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2876.
Abstract 288: Revisiting small molecules that influence the nuclear translocation of thioredoxin-1, prohibitin, and galectin-3 for cancer chemotherapy
Authors: Fortin Jessica S. , Wineland Thomas E. , Duggan Kelsey E. , C.-Gaudreault René 
Published: July 2021

Abstract
Phenyl-3-(2-chloroethyl)ureas (CEU) are alkylating agents exhibiting potent antiproliferative properties both in vitro and in vivo. CEUs' cytoxicity is not influenced by hypoxia or other clinically relevant mechanisms of chemoresistance, such as alteration of topoisomerase II activity and increased P-glycoprotein over-expression, DNA repair, intracellular gluthatione-S-transferase activity. A first subset of CEU exemplified by the prototypical molecules 4-tert-butyl-CEU (tBCEU) and 4-iodo-CEU (ICEU) have been shown to alkylate the colchicine-binding site on βII-tubulin. In parallel, these molecules disrupted the cytoskeleton and arrested the cell cycle in G2/M leading to anoikis. So far we have conducted several structure-activity relationship and molecular pharmacology studies in an attempt to refine the specificity of CEU for β-tubulin and the colchicine-binding site. Unexpectedly, a prototypical molecule designated as 1-(2-chloroethyl)-3-(4-cyclohexylphenyl)urea (cHCEU) emerged as arresting the cell cycle in G0/G1 phase instead of G2/M. Experiments using [14C-urea]-cHCEU showed its binding to thioredoxin isoform-1 (Trx-1) and prohibitin (PHB), but not β-tubulin. Complementary immunocytofluorometry experiments clearly showed the abrogation of the nuclear translocation of Trx-1 from the cytosol. We report herein that in addition to Trx-1 and PHB, cHCEU also alkylates galectin-1 and -3 isoforms. The cellular localization of thioredoxin-1, prohibitin, and galectin-3 (Gal-3) is changed following cHCEU treatment. In addition, the expression of Trx-1, PHB, and Gal-3 seems unaffected by CEU and its analogues. Interestingly, these proteins are all known to play an important role in the cell cycle regulation through various mechanisms. The mechanism(s) underlying the effect of cHCEU on protein translocation is unknow and might be relevant to design new potent anticancer drugs that will target specific and lethal biological pathways essential to tumor growth.
Citation Format: Jessica S. Fortin, Thomas E. Wineland, Kelsey E. Duggan, René C.-Gaudreault. Revisiting small molecules that influence the nuclear translocation of thioredoxin-1, prohibitin, and galectin-3 for cancer chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 288.
Abstract 2881: Snail-mediated regulation of MMP1 expression in the context of ovarian cancer invasiveness
Authors: Suzuki Tise , Curow Casey , Wang Hanmin , Martinez Asis , Hojo Nozomi , Unternaehrer Juli 
Published: July 2021

Abstract
Ovarian cancer ranks fifth among the causes of cancer death in US women. Despite initial positive response to cytoreductive surgery and chemotherapy treatments with platinum-based therapies, over 80% of patients with high-grade serous ovarian cancer (HGSOC), the most common type of ovarian cancer, exhibit relapse. Most recurrent cases of HGSOC are resistant to chemotherapy, and cells are highly invasive. Therefore, further studies are required to understand the mechanisms of invasiveness and chemoresistance in relapse patients. In HGSOC, invasiveness can result when epithelial cancer cells undergo epithelial-mesenchymal transition (EMT). The transcription factor SNAI1 (Snail) initiates the EMT process and increased Snail expression can result in enhancement of metastatic potential, acquisition of stem cell-like characteristics, and resistance to chemotherapeutic drugs. However, the mechanism of activation of invasiveness in ovarian cancer by Snail has not been defined. In OVCAR8, a HGSOC cell line, comparison of shSnail knockdown to control through RNA-sequencing revealed that Snail expression is directly correlated to matrix metalloprotease 1 (MMP1) expression. MMP1 is an extracellular matrix remodeler known to digest interstitial collagens. High MMP1 expression has been linked to increased cancer invasion, metastasis, angiogenesis, and apoptosis. Furthermore, in breast cancer, MMP1 has been reported to be a downstream target of Slug, another major EMT transcription factor. Some evidence for Snail activation of MMPs in liver cancer has been presented, but a direct relationship has not been established. Therefore, we hypothesize that overexpression of Snail in ovarian cancer cells results in MMP1 upregulation, leading to increased invasion. RT-qPCR was performed to analyze relative mRNA expression levels of Snail and MMP1 in eight cell lines. We found that Snail and MMP1 levels were higher in the more mesenchymal-like cell lines, some of which are known to be more invasive. Additionally, Snail overexpression led to a significant corresponding increase in MMP1 mRNA expression and resistance to cisplatin. Chromatin immunoprecipitation (ChIP) experiments demonstrate Snail binding to the MMP1 promoter. Thus, our preliminary findings have shown strong evidence of a Snail-mediated regulation of MMP1 expression in the context of HGSOC invasiveness.
Citation Format: Tise Suzuki, Casey Curow, Hanmin Wang, Asis Martinez, Nozomi Hojo, Juli Unternaehrer. Snail-mediated regulation of MMP1 expression in the context of ovarian cancer invasiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2881.
Abstract 2898: Rac1 as a driver and therapeutic target in ovarian cancer
Authors: Rivera Melanie , Grimes Martha M. , Hudson Laurie G. , Wandinger-Ness Angela 
Published: July 2021

Abstract
Aberrant Rac1 signaling contributes to cancer growth and metastasis, therefore, we investigated the effect of altering Rac1 expression and activity to pinpoint which metastatic processes and tumor microenvironment immune factors are influenced by Rac1 signaling. We have identified that the R- enantiomer of ketorolac, a drug given for pain management, is a Rac1 and Cdc42 selective inhibitor. In a retrospective study, we found that treatment with racemic ketorolac significantly increased the survival probability of ovarian cancer patients. RNA seq analyses of ascites tumor cell samples from ovarian cancer patients in a prospective study receiving racemic ketorolac for clinically indicated use in pain relief, showed significant downregulation of genes involved in endocytosis, regulation of actin cytoskeleton, ER protein processing, TNF and NOD signaling. To further distinguish the activities most directly regulated by Rac1 and important in ovarian cancer, we tested the impact of manipulating the expression of Rac1 in ovarian cancer cells on adhesive and invasive cell behaviors, as well as the impacts of gene expression relative to ketorolac treatment. Using electric cell-substrate impedance sensing (ECIS), Rac1 overexpression resulted in increased cell-cell barrier formation and cell adhesion. Whereas, CRISPR-CAS9 mediated knockdown of Rac1 resulted in decreased cell adhesion. Using Matrigel invasion chambers and mesothelial clearance assays, Rac1 overexpression led to increased ovarian cancer cell invasion when compared to parental and Rac1 knockdown cell lines. Furthermore, intraperitoneal growth of ovarian cancer cells overexpression Rac1 relative to parental control lines increased tumor burden in vivo. Conversely, with knockdown of Rac1, tumor burden and omental adhesion was decreased, as quantified using IVIS bioluminescence imaging. RNA seq analyses of tumors manipulated for Rac1 as compared to R-ketorolac will be presented. The composite data indicate that targeting Rac1 in ovarian cancer with R-ketorolac or otherwise has therapeutic benefit in decreasing tumor cell dissemination and metastasis.
Citation Format: Melanie Rivera, Martha M. Grimes, Laurie G. Hudson, Angela Wandinger-Ness. Rac1 as a driver and therapeutic target in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2898.