bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1835: Nqo1 ablation inhibits activation of the PI3K/Akt and MAPK/ERK pathways and blocks metabolic adaptation in hepatocellular carcinoma
Authors: Dimri Manali , Humphries Ashley , Laknaur Archana , Elattar Sawsan , Sharma Ashok , Kolhe Ravindra , Satyanarayana Ande 
Published: August 2019

Abstract
According to the World Health Organization, hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer related deaths worldwide. HCC is highly resistant to conventional
chemotherapies; therefore, identification of specific molecular targets for the development of targeted therapies is indispensable. Cancer cells undergo metabolic adaptation to sustain uncontrolled proliferation and depends on the high rate of glycolysis and glutaminolysis. Hence, identifying and targeting proteins that assist cancer cells in metabolic reprogramming is an effective strategy to block their proliferation. We detected a strong upregulation of NAD(P)H Quinone Dehydrogenase 1 (Nqo1), a cytosolic flavoprotein, in vivo in mouse and human liver tumors as well as in liver cancer cell lines in vitro. Knockdown of Nqo1 in liver cancer cells by shRNA caused a significant downregulation of both glycolytic and glutaminolysis genes, impaired cell proliferation, colony formation and in vivo xenograft tumor growth. Nqo1-/- mice with HCC displayed significant reduction in tumor number, size and growth. In Nqo1+/+ mice, histological analysis of liver tumors revealed large tumor cells with hyperchromatic nuclei in a compact growth pattern, whereas Nqo1-/- livers appeared normal. Hyper-activated PI3K/Akt and MAPK/ERK signaling pathways play central role in cancer cell metabolic adaptation since their downstream effectors such as Akt and c-Myc control most of the glycolytic and glutaminolysis genes. Interestingly, at the molecular level, Nqo1 knockdown caused strong upregulation of the tumor suppressor PTEN, and enhanced activation of the serine/threonine phosphatase PP2A, leading to impaired activation of the PI3K/Akt and MAPK/ERK/c-Myc pathways. Our findings indicate that, by targeting PP2A and PTEN, Nqo1 enhances the expression and/or activity of PDK1, Akt, ERK1/2 and c-Myc and promotes cancer cell metabolic reprogramming and hence may function as a key therapeutic target for HCC inhibition.
Citation Format: Manali Dimri, Ashley Humphries, Archana Laknaur, Sawsan Elattar, Ashok Sharma, Ravindra Kolhe, Ande Satyanarayana. Nqo1 ablation inhibits activation of the PI3K/Akt and MAPK/ERK pathways and blocks metabolic adaptation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1835.
Abstract 1853: Association of IDH genes with prostate cancer progression and their regulation by the androgen receptor
Authors: Gonthier Kevin , Poluri Raghavendra TK , Weidmann Cindy , Audet-Walsh Etienne 
Published: August 2019

Abstract
A primary function of the prostate is to synthesize and secrete high levels of citrate by way of a unique metabolic profile regulated by the androgen receptor (AR). Prostate cancer (PCa) is an androgen-dependent disease that is characterized by early reprogramming of citrate metabolism. Accordingly, mutations of the isocitrate dehydrogenase genes IDH1 and IDH2, which are key enzymes involved in the regulation of cellular citrate levels, have been demonstrated as important oncogenic events in several cancer types, including in about 3% of all PCa cases. However, if IDH1 and other IDH isoforms are associated with PCa progression as well as the regulatory factors controlling their expression remain mostly unknown. Across the human cancer spectrum, PCa appears to be the cancer type with the highest expression of IDH1, with levels even higher than common cancers associated with IDH1 mutations such as gliomas. Using publicly available datasets and quantitative PCR, we showed that IDH1 is the predominant IDH isoform expressed in PCa cells. In PCa, the androgen receptor was found to regulate several IDH isoforms in both in vitro and in vivo models of PCa, predominantly positively regulating IDH1. Chromatin immunoprecipitation experiments confirmed the recruitment of AR at several regulatory regions of IDH1 and IDH2. IDH1 and other IDH isoforms were shown to be significantly altered during PCa progression, which is consistent with a reprogramming of citrate metabolism in PCa. In addition, modulation of IDH expression significantly altered PCa cell proliferation and metabolism. Overall, our study indicates that IDH gene regulation is associated with PCa progression and that AR plays a significant role in the regulation of IDH genes.
Citation Format: Kevin Gonthier, Raghavendra TK Poluri, Cindy Weidmann, Etienne Audet-Walsh. Association of IDH genes with prostate cancer progression and their regulation by the androgen receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1853.
Abstract 1866: Sea cucumber (Stichopus japonicas) F2 enhanced TRAIL-induced apoptosis via XIAP ubiquitination-ER stress in colorectal cancer cells
Authors: Kim Jung lim , Park Seong Hye , Jeong Soyeon , Kim Bo Ram , Na Yoo Jin , Jo Min Jee , Jeong Yoon A , Yun Hye Kyeong , Kim Dae Yeong , Kim Bu Gyeom , Oh Sang Cheul , Lee Dae-Hee 
Published: August 2019

Abstract
Natural products have shown great promise in sensitizing cells to TNF-related apoptosis-inducing ligand (TRAIL) therapy. Sea cucumber (SC) extracts possess antitumor activity, and hence their potential to sensitize CRC cells to TRAIL therapy was evaluated. This study used Western blotting to evaluate the combination effects of SC and TRAIL in CRC and determined the molecular mechanism underlying these effects. SC fractions and TRAIL alone had no effect on apoptosis; however, combined treatment dramatically induced apoptosis of CRC cells, but not normal colon cells. Combined treatment induced expression of apoptotic proteins (poly (ADP-ribose) polymerase (PARP), caspase 3, and 8), and this effect was markedly inhibited by ubiquitination of X-linked inhibitor of apoptosis protein (XIAP). SC did not affect the mRNA levels, but increased proteasomal degradation and ubiquitination of XIAP protein. Furthermore, SC induced reactive oxygen species (ROS) production, thereby activating c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER) stress-related apoptotic pathways in CRC. Taken together, our results demonstrate that the SC fraction may sensitize CRC cells to TRAIL-induced apoptosis through XIAP ubiquitination-ER stress.
Citation Format: Jung lim Kim, Seong Hye Park, Soyeon Jeong, Bo Ram Kim, Yoo Jin Na, Min Jee Jo, Yoon A Jeong, Hye Kyeong Yun, Dae Yeong Kim, Bu Gyeom Kim, Sang Cheul Oh, Dae-Hee Lee. Sea cucumber (Stichopus japonicas) F2 enhanced TRAIL-induced apoptosis via XIAP ubiquitination-ER stress in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1866.
Abstract 1874: A ZEB1-regulated EMT transcriptional program is associated with early nodal metastasis and improved survival for stage N2/N3 breast cancer patients
Authors: Block C James , Wu Guojun 
Published: August 2019

Abstract
The epithelial-to-mesenchymal transition (EMT) is a transcriptionally-mediated process by which epithelial cells cease expression of cell-cell junction proteins, lose polarity, and begin expressing mesenchymal cytoskeletal and extracellular matrix components. While EMT is critical for normal development and wound healing, this process has been experimentally shown to be pathologically activated in cancer cells, leading to enhanced migratory and invasive capabilities, increased chemoresistance, and distant metastasis in mouse models. Consequently, EMT has been hypothesized to be a driving factor in metastatic progression and tumor recurrence in multiple cancer types, including breast cancer. EMT can be driven by several transcription factors (EMT-TFs) which are independently capable of inducing EMT and can regulate each other. Our group set out to identify EMT-TFs which were commonly activated across EMT models. By performing integrative analysis of multiple datasets, we determined that the EMT-TF ZEB1 demonstrates the most reproducible and consistent association with EMT in experimental models, breast cancer cell lines and in breast cancer patients. We then identified a high-confidence set of genes commonly upregulated in EMT and regulated by ZEB1. We observed that this ZEB1-associated transcriptional program is highly enriched for genes overexpressed in patients with early-stage node metastases compared to patients without lymph node involvement. Paradoxically, we observe that ZEB1 and ZEB1 associated genes exhibit higher expression in adjacent normal tissue samples than in primary tumor samples. Additionally, we discovered a reproducible association between ZEB1 and ZEB1-program gene expression and significantly improved recurrence-free and overall survival for breast cancer patients with distant lymph node involvement. This association was unique to ZEB1, as other EMT-TFs did not predict survival in these patients. In conclusion, our data demonstrate that the ZEB1-driven EMT program may contribute to early nodal metastasis, but that sustained ZEB1 expression may ultimately suppress cancer progression and improve survival. These findings may help clarify the specific contributions of different EMT-TFs to breast cancer progression.
Citation Format: C James Block, Guojun Wu. A ZEB1-regulated EMT transcriptional program is associated with early nodal metastasis and improved survival for stage N2/N3 breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1874.
Abstract 188: The oncometabolite d-2-hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway
Authors: Lee You Mie , Seok Jiyoon , Yoon Soo-Hyun , Lee Sun-Hee , Jung Jong Hwa 
Published: August 2019

Abstract
Mutation of isocitrate dehydrogenase (IDH) 1 (R132H) and IDH2 (R172K) and induction of hypoxia in various solid tumors results in changes to metabolic profiles, including production of the d- or l-forms of 2-hydroxyglutarate (2HG) from α-ketoglutarate in aerobic metabolism in the TCA cycle. However, it is unclear whether the oncometabolite d-2HG increases angiogenesis in endothelial cells. Therefore, in this study, we analyzed the levels of various metabolites, including d-2HG, under hypoxic conditions and in IDH2R172K mutant breast cancer cells by mass spectrometry. We then further evaluated the effects of this metabolite on angiogenesis in breast cancer cells. Our results showed that treatment with d-2HG increased the levels of secreted vascular endothelial growth factor (VEGF) in cancer cells and enhanced endothelial cell proliferation in a concentration-dependent manner. Wound healing and transwell migration were significantly increased by d-2HG to a level similar to that induced by VEGF. Tube formation was significantly stimulated by d-2HG, and chick chorioallantoic membrane angiogenesis was also enhanced by d-2HG. d-2HG activated VEGF receptor (VEGFR) 2 and VEGFR2 downstream signaling, extracellular signal-regulated kinase 1/2, focal adhesion kinase, AKT, and matrix metalloproteinase (MMP) 2. Taken together, our results suggested that d-2HG induced angiogenic activity via VEGFR2 signaling and increased MMP2 activity.
Citation Format: You Mie Lee, Jiyoon Seok, Soo-Hyun Yoon, Sun-Hee Lee, Jong Hwa Jung. The oncometabolite d-2-hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 188.
Abstract 1883: Ovarian cancer cells overcome the cytotoxic effect of cisplatin by hyper activating CCR9-mediated signaling in response to cisplatin
Authors: Mir Hina , Kapur Neeraj , Singh Shailesh 
Published: August 2019

Abstract
Ovarian cancer (OC) has highest mortality rate among the gynecological malignancies. Chemotherapies, in combination with surgery, are standard treatment offered to the patients with advanced OC. Although 80% patients initially respond to platinum-based chemotherapy, clinical responses remain short-lived due to chemoresistance. Most patients experience relapse and 50-60% of them die within 5 years. Therefore, development of novel therapies for OC remains a high priority. Hence, the major focus of this study is to define the biology of CCR9, which is highly expressed in OC in response to platinum drug. Effect of cisplatin on CCR9 expression and impact of CCR9 activation on molecular and cellular changes involved in overcoming the effect of cisplatin was determined by flow cytometric and western blot analyses. Our data show higher expression of CCR9 and CCL25 in OC cells in response to cisplatin treatment. Additionally, our data show higher expression and activation of estrogen receptor-α (ER- α) in OC cell after CCR9 activation. In addition to this, we show CCR9-mediated expression of Smoothened (SMO) known to support stem cell like phenotype by activating Hedgehog signaling and co-expression of CD44 and CCR9 as well as higher CD44 expression in OC cells following CCL25 treatment. CCR9-CCL25 axis promoted epithelial to mesenchymal transition. These observations strongly show an association of CCR9-CCL25 axis in OC pathogenesis, therapeutic resistance, and chemotherapeutic efficacy.
Citation Format: Hina Mir, Neeraj Kapur, Shailesh Singh. Ovarian cancer cells overcome the cytotoxic effect of cisplatin by hyper activating CCR9-mediated signaling in response to cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1883.
Abstract 1891: Oncogenic MDM2-containing exosomes promote pre-metastatic niche establishment
Authors: Casadei Lucia , Calore Federica , Deshmukh Ameya , Zewdu Abeba , Braggio Danielle A. , Fadda Paolo , Wabitsch Martin , Lopez Gonzalo , Leight Jennifer , Lev Dina , Croce Carlo M. , Pollock Raphael E. 
Published: August 2019

Abstract
Extracellular vesicles (EVs) have an important role in the communication between cells for their ability to transfer proteins and other biologically active molecules. EVs have been also described to have unique functions during pre-metastatic niche establishment and maintenance. MDM2 oncoprotein is the best-characterized cellular antagonist of p53 and its amplification is one of the most known mechanisms for tumor development. MDM2 amplification occurs in more than forty different types of malignancies and in 100% of well-differentiated and dedifferentiated liposarcoma (DDLPS). Retroperitoneal DDLPS is especially concerning given its propensity for multifocal local and distant recurrence, accounting for an overall survival rate of 10% at 10 years. Here, we show the presence of MDM2 in tumor EVs and specifically in both DDLPS cell line-derived EVs and patient-serum EVs. We also show the ability of MDM2-cargo to be transferred to recipient preadipocytes. Furthermore, we also demonstrated that this transfer is able to promote a pre-metastatic niche establishment in the DDLPS tumor microenvironment fat bearing areas, inducing: (I) tumor associated phenotype such as enhanced proliferation and migration, in the recipient preadipocytes, by downregulation of MDM2 downstream pathway; (II) pro-inflammatory phenotype through the release of pro-inflammatory cytokines such as IL-8; (III) release of active metalloproteinases such as MMP2 which is crucial for the invasiveness of many disseminating tumors. In conclusion here we report the presence of MDM2, in the patient circulation; importantly showing that MDM2 triggers the release of active MMP-2, we also propose a possible mechanism for pre-metastatic niche establishment and DDLPS multifocal loco-regional recurrence.
Citation Format: Lucia Casadei, Federica Calore, Ameya Deshmukh, Abeba Zewdu, Danielle A. Braggio, Paolo Fadda, Martin Wabitsch, Gonzalo Lopez, Jennifer Leight, Dina Lev, Carlo M. Croce, Raphael E. Pollock. Oncogenic MDM2-containing exosomes promote pre-metastatic niche establishment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1891.
Abstract 1917: High-throughput evaluation of treatment response in patient-derived glioma stem cell models
Authors: Zhang Ze-yan , Ding Yingwen , Ezhilarasan Ravesanker , Yang Jie , Long Lihong , Bronk Lawrence , Wang Qianghu , Sulman Erik P. 
Published: August 2019

Abstract
Although significant progresses in molecular oncology are being made using conventional cell lines, most therapies still fail in phase III clinical trials. Patient-derived models are being used more frequently as they are more faithfully representing the genomic features of primary tumors. However, one by one test of each model from large biobanks is extremely economy and time consuming. In this study, each of a panel of patient-derived glioblastoma stem cell (GSC) models was uniquely tagged by a lentiviral Cas9D10A and paired-gRNA targetable unique reporter (CAPTURE) barcoding system. Barcoded GSCs were then pooled evenly and following by radiation treatment (RT) in vitro. Amplicon sequencing was employed to count the barcodes distribution, which represent the relative cell number. The results showed that this approach faithfully identified the RT resistant GSCs from a mixing pool when comparing to the results from canonical clonogenic assay. In addition, a fluorescence marker will be switched by delivery of corresponding barcodes targeting CRISPR so that we can re-isolate interested cell models from the treated pool for investigating the treatment sensitivity and resistance mechanism. This study will provide a robust approach for therapeutic discovery take advantage of patient-derived models from large biobanks.
Citation Format: Ze-yan Zhang, Yingwen Ding, Ravesanker Ezhilarasan, Jie Yang, Lihong Long, Lawrence Bronk, Qianghu Wang, Erik P. Sulman. High-throughput evaluation of treatment response in patient-derived glioma stem cell models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1917.
Abstract 1969: Role of the CXCL17-CXCR8 (GPR35) axis in cutaneous squamous cell carcinoma
Authors: Khandelwal Alok R. , Alam Md Maksud , Moore-Medlin Tara , Savage Hillary A. , Nathan Cherie-Ann O. 
Published: August 2019

Abstract
Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin and is the second-most commonly diagnosed form of skin cancer (16%) striking 200,000 Americans annually. Increased exposure to Ultraviolet-B (UVB) from solar radiation as a result of the depletion of the ozone layer and the widespread use of tanning beds are the primary reasons for the increased incidence of cSCC. Novel mechanism-based therapeutics are needed to prevent UVB-induced cSCC. Chemokines are a group of small chemotactic cytokines that can exert extensive and complex effects on cancer via interaction with their receptors. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest member of the chemokine family, and recent studies have identified both a causative and suppressive role of CXCL17 and its cognate receptor GPR35 in tumorigenesis. The purpose of this study was to determine the role of CXCL17 and GPR35 in the pathogenesis of cSCC. CXCL17 and GPR35 were significantly overexpressed in cSCC cells (SCC12A and SCC118) compared to HaCaT cells. Stimulation with CXCL17 significantly induced cSCC cell proliferation, migration, and motility suggesting an essential role in tumor growth, invasion, and metastasis. Tumor-specific overexpression of CXCL17 was detected in human cSCC and UVB-induced mouse cSCCs that further bolsters our in vitro findings. Recent studies have also identified the role of CXCL17 in tumor cell infiltration and immune invasion leading to tumor progression. In our preliminary studies, increased expression of CXCL17 in cSCC correlated with an augmented number of CD3+, CD4+ and CD8+ T-cells infiltrates. Our data suggest that CXCL17 could potentially exert differential effects based on cell types in the tumor microenvironment. Our studies underscore the importance of CXCL17/GPR35 signaling in cSCC and provide a novel target for the treatment of non-melanoma skin cancer.
Citation Format: Alok R. Khandelwal, Md Maksud Alam, Tara Moore-Medlin, Hillary A. Savage, Cherie-Ann O. Nathan. Role of the CXCL17-CXCR8 (GPR35) axis in cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1969.
Abstract 1985: Reassessment of exosome composition
Authors: Jeppesen Dennis K. , Franklin Jeffrey L. , Higginbotham James N. , Zhang Qin , Coffey Robert J. 
Published: August 2019

Abstract
The heterogeneity of small extracellular vesicles and the presence of non-vesicular extracellular matter is a major obstacle to the study of exosomes. Here we employ two complementary methods, high-resolution density gradient fractionation and direct immunoaffinity capture, to demonstrate separation of small extracellular vesicles from non-vesicular material, and exosomes from other types of small extracellular vesicles. Cells secrete Argonaute 1-4 independently of exosomes. Extracellular RNA and RNA-binding proteins are differentially expressed between exosome and non-vesicle compartments. Exosomes do not possess a cytoskeleton and exclude glycolytic enzymes. Annexin A1 is a novel and specific membrane-associated protein marker of microvesicles shed directly from the cell plasma membrane, distinct from exosomes in vitro and in vivo. Small extracellular vesicles are not vehicles of active DNA release. Instead we propose a new model for active secretion of extracellular DNA through an autophagy- and multivesicular endosome-dependent but exosome-independent mechanism. A reassessment of exosome composition is necessary.
Citation Format: Dennis K. Jeppesen, Jeffrey L. Franklin, James N. Higginbotham, Qin Zhang, Robert J. Coffey. Reassessment of exosome composition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1985.