tbuckley/cabot-search huggingface dataset:
Abstract 1917: AXL inhibition in ovarian cancer stem-like cells increases chemo-sensitivity
Authors: Jin-Young Kim, Hyewon Chung, So-Jin Shin, Eunyoung Ha, Chi-Heum Cho
Journal: Cancer Research (2017)

Abstract Cancer stem-like cells (CSCs), a small population of cancer cells with regenerative potential, may lead to the initiation and progression of secondary tumors. Long-term chemotherapeutic drug treatment can also result in the generation of a drug resistant population of cancer stem cells. In this study we have isolated CD44+ and CD117+ enriched ovarian cancer stem-like cells from primary cultured ascites cells removed from ascites fluid of naïve ovarian cancer patients. AXL, a type I receptor tyrosine kinase family member, is found to be over-expressed in ovarian cancer stem-like cells. Cell viability assays showed that ovarian CSCs are chemo-resistant to concentration dependent paclitaxel treatment. AXL was inhibited using a R428 and cell viability assays and apoptotic assays in the presence of paclitaxel were performed, which made the CSCs chemo sensitive. Si-RNA based inhibition of AXL also displayed a similar pattern of improving the sensitivity of the stem-like cells to the chemotherapeutic drug. PI3-kinase/Akt signaling pathway has also been shown to be involved in decreasing the cell viability during the inhibition of AXL. In conclusion, this study establishes the role of AXL, a receptor tyrosine kinase, as one of the key proteins influencing the chemo resistance in ovarian cancer stem-like cells. Citation Format: Jin-Young Kim, Hyewon Chung, So-Jin Shin, Eunyoung Ha, Chi-Heum Cho. AXL inhibition in ovarian cancer stem-like cells increases chemo-sensitivity [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 1917. doi:10.1158/1538-7445.AM2017-1917
Abstract 1502: The link between NRF2 and mitochondria through the regulation of miR-181c/mitochondria-encoded cytochrome c oxidase subunit-1
Authors: Mi-Kyoung Kwak, Kyeong-Ah Jung, Donghyeok Kim, Sujin Lee
Journal: Cancer Research (2017)

Abstract The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is involved in the environmental resistance of cancers by enhancing the antioxidant capacity. In the current study, we investigated the potential link between NRF2 and mitochondrial function in cancer cells. Global miRNA expression analysis of HT29 and HCT116 identified miR-181c as an NRF2-silencing-inducible miRNA, and miR-181c elevation was associated with the decrease in mitochondria-encoded cytochrome c oxidase subunit-1 (MT-CO1), a mitochondrial genome-encoded complex IV subunit of the electron transport chain. As a result of decreased complex IV activity, NRF2-silenced cancer cells exhibited reduced levels of mitochondrial membrane potential (MMP), oxygen consumption rate, and ATP production. Notably, these changes induced adaptive activation of AMP-activated protein kinase-α (AMPKα) and thereby, NRF2-silenced cells were more vulnerable to AMPK inhibitor-induced growth suppression. Similarly, mouse tumor xenografts derived from NRF2-silenced HT29 exhibited MT-CO1 reduction and AMPKα activation, thereby increasing responsiveness to the AMPK inhibitor treatment. Collectively, we showed a novel link of NRF2 to cancer mitochondria and AMPK signaling by elucidating miR-181c/MT-CO1 signaling as an underlying molecular mechanism. These results also suggest that it may an effective strategy to inhibit both NRF2 and AMPK to control adaptive tumor responses. Citation Format: Mi-Kyoung Kwak, Kyeong-Ah Jung, Donghyeok Kim, Sujin Lee. The link between NRF2 and mitochondria through the regulation of miR-181c/mitochondria-encoded cytochrome c oxidase subunit-1 [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 1502. doi:10.1158/1538-7445.AM2017-1502
Abstract 3510: A role for the Ewing’s sarcoma breakpoint protein EWS in ERG-induced prostate tumorigenesis
Authors: Vivekananda Kedage, Nagarathinam Selvaraj, Taylor R. Nicholas, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst
Journal: Cancer Research (2017)

Abstract The TMPRSS2-ERG gene fusion occurs in one-half of prostate tumors and results in expression of ERG, an ETS family transcription factor that promotes prostate tumorigenesis. Another 5-10% of prostate tumors have similar rearrangements that result in over-expression of other ETS family members such as ETV1, ETV4, and ETV5. However, not all ETS family members are oncogenic, and normal prostate cells express at least 15 of these other ETS factors. Therefore, it is important to understand mechanisms that differentiate oncogenic ETS factors from non-oncogenic ETS factors. We have recently discovered that ERG, ETV1, ETV4, and ETV5, and no other ETS factor can directly bind the protein EWS. This is striking, as EWS is fused to various ETS factors in the chromosomal rearrangements that cause Ewing’s sarcoma. We demonstrate that fusion of EWS to any ETS protein is sufficient for that protein to function like ERG in prostate cells. Furthermore, the EWS-ERG interaction is required for ERG to activate an oncogenic gene expression program and for ERG-mediated tumorigenesis. Therefore, these findings reveal a conserved oncogenic mechanism for prostate cancer and Ewing’s sarcoma. In prostate cancer, aberrant over-expression of an ETS factor that naturally interacts with EWS, brings EWS to ETS-bound regions. In Ewing’s sarcoma this interaction is forced by the presence of an EWS/ETS fusion protein. Therefore, this model predicts that treatments that target EWS function would be effective in both types of cancer. Citation Format: Vivekananda Kedage, Nagarathinam Selvaraj, Taylor R. Nicholas, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst. A role for the Ewing’s sarcoma breakpoint protein EWS in ERG-induced prostate tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3510. doi:10.1158/1538-7445.AM2017-3510
Abstract 1408: LIM protein Ajuba participates in the ATR response by direct interaction with RPA70
Authors: Sandy Wan S. Fowler, Diego Loayza, Pascal Maguin
Journal: Cancer Research (2017)

Abstract DNA damage response (DDR) pathways are essential for genome stability and cell survival. Specifically, the ATR kinase is activated by DNA replication stress or UV irradiation. An early event in this activation is the phosphorylation and local recruitment of RPA, a single strand DNA binding protein. Our lab has shown that the LIM protein Ajuba associates with RPA, an OB fold-containing protein, and this interaction prevents an unscheduled ATR response. We hypothesize that Ajuba represses the ATR pathway through direct interaction with RPA, thereby preventing activation of ATR. To test this hypothesis, we employed E. coli and in vitro translation system for the production of recombinant proteins. Our data show that Ajuba directly associates with the large subunit of RPA, RPA70. The domains involved in the interaction were the C-terminal OB folds of RPA70, and the region between the PreLIM and LIM domains in Ajuba. We speculate that this interaction mediates the association of Ajuba with the RPA complex in cells. Understanding the implication of the Ajuba and RPA interaction will allow us to gain insights on the regulation of DDR, which is involved in early events of cellular transformation and tumorigenesis in human cells. Citation Format: Sandy Wan S. Fowler, Diego Loayza, Pascal Maguin. LIM protein Ajuba participates in the ATR response by direct interaction with RPA70 [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 1408. doi:10.1158/1538-7445.AM2017-1408
Abstract 1462: Exosome-derived miR-429 contributes to prostate cancer chemoresistance
Authors: Yang Liu, Liye Xie, Jing Li, Atsushi Mizokami, Evan T. Keller, Yi Lu, Jian Zhang
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the most common cancer in men and the 2nd leading cause of cancer-related death in the United States. Certain miRNAs, act as tumor promoting or inhibiting factors in tumor development, function primarily by targeting specific mRNAs for degradation or inhibition of translation of their targeted proteins. Emerging evidence indicates that exosomes play a key role in tumor-host crosstalk, and exosome secretion, composition, and functional capacity are altered as tumors progress to aggressive phenotypes. From our prior report, we have constructed a potential network of 29 deregulated miRNAs, including 19 up and 10 down, in exosome samples derived from two kinds of paclitaxel resistant PCa cells (PC3-TXR and DU145-TXR) compared with their parental cells (PC3 and DU145). In this study, to further determine the roles of certain miRNAs derived from exosomes in chemoresistant cells, we firstly confirmed the lower expression level of miR-429 miRNA in the exosomes derived from the paclitaxel resistant PCa cells compared to their parental cells. In addition, when the miR-429 was over-expressed in PC3-TXR and DU145-TXR cells by stable transfection, epithelial-to-mesenchymal transition (EMT) markers significantly altered together with morphological changes. Overexpression of miR-429 decreased the tumor cell migration and invasion that associated with inactivation of PI-3K/AKT and Notch signaling pathways since the pathway specific inhibitors significantly diminished the transfected tumor cell migration and invasion. Finally, we found that overexpression of miRNA-429 significantly enhanced chemo-sensitivity of the chemoresistant PCa cells. These data suggested that exosome-derived miR-429 contributes to PCa chemoresistance and miR-429 may become a potential therapeutic target for PCa patients. This work was supported by Natural Science Foundation of China (NSFC) Key Project (81130046); NSFC (81171993; 81272415); Guangxi Projects of China (2013GXNSFEA053004; 2012GXNSFCB053004; 2013GXNSFBA019177; 1355004-5; 201201ZD004; GZPT13-35; 14122008-22; 11-031-05-K2; KY2015YB057; 14-045-12-K2). Note: This abstract was not presented at the meeting. Citation Format: Yang Liu, Liye Xie, Jing Li, Atsushi Mizokami, Evan T. Keller, Yi Lu, Jian Zhang. Exosome-derived miR-429 contributes to prostate cancer chemoresistance [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 1462. doi:10.1158/1538-7445.AM2017-1462
Detection of multidrug-resistant bacteria in the occupied Palestinian territory: a cross-sectional study
Authors: Isabella Sjölander, Frank Hansen, Abdelraouf Elmanama, Rasha Khayyat, Alaeddin Abu-Zant, Ayman Hussein, Adham Abu Taha, Anette M Hammerum, Oana Ciofu
Journal: The Lancet (2017)
Abstract 5774: Effect of extrinsic and intrinsic solid stress on tumor spheroid growth
Authors: Ludivine Guillaume, Annaick Desmaison, Bernard Ducommun, Valérie Lobjois
Journal: Cancer Research (2017)

Abstract Growth-induced intrinsic solid stress and adaptive response to extrinsic mechanical cues have been recognized as major hurdles to overcome in cancer treatment and any approach that could significantly modulate these parameters would have an impact in improving therapies. An attracting in vitro model to explore this issue is the Multicellular Tumor Spheroid, a 3D culture model reproducing the non-vascularized microtumor environment, proliferation gradient and cellular interactions. To explore and assess spheroid growth-induced solid stress, we couple biological approach to the application of mechanics and modeling. We adapted a method, which consist in partial sectioning of the microtumor and measuring tissue relaxation parameters. Using this strategy, we showed that cell proliferation induced the accumulation of intrinsic mechanical constraint. To investigate the consequence of the accumulation of solid stress at the cell scale, we analyzed 3D cellular organization within spheroids. Using 3D light sheet microscopy (LSM) visualization on optically cleared spheroids combined with 3D reconstruction and automatic algorithms, we were able to determine cell density, nuclear orientation and nuclear shape in whole 3D spheroids. We found that stress accumulation is associated with an increase in cell density and a regionalization of nuclei organization. We also explored the impact of extrinsic stress in 3D culture condition under constraint. We found that mechanical constraint and cytoskeleton control nuclei orientation and using live 3D LSM microscopy we show that mechanical constraint induces an actin cytoskeleton-dependent prometaphase delay. We anticipate that this work will provide key information and parameters to improve our knowledge of the crosstalk between mechanical parameters and tumor growth. Citation Format: Ludivine Guillaume, Annaick Desmaison, Bernard Ducommun, Valérie Lobjois. Effect of extrinsic and intrinsic solid stress on tumor spheroid growth [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 5774. doi:10.1158/1538-7445.AM2017-5774
Abstract 5129: Cell-penetrating doxorubicin released from Elastin-like polypeptide kills doxorubicin-resistant cancer cells
Authors: Jung Su Ryu, Drazen Raucher
Journal: Cancer Research (2017)

Abstract A drug-releasing system facilitated by external stimuli could be used to deliver cytotoxic chemotherapy agents to tumor sites selectively and safely. Among many suggested strategies, elastin-like polypeptide (ELP) exploits its characteristic of phase transitioning in response to changes in ambient temperature. This unique property permits selective targeting of the polymer to hyperthermic tumors by aggregating as it transitions. ELP therefore can be used as a thermosensitive vector for the delivery of chemotherapy agents and therapeutic peptides, resulting in a rise in drug concentration exclusively in tumors. This novel strategy introduces unprecedented options for treating cancer, with fewer concerns about indiscriminate side effects from the chemotherapy. In this study, the ELP-drug conjugate was further modified with incorporation of an enzyme-specific cleavable linker in order to trigger drug release within tumors. The suggested system is composed of ELP, a matrix metalloproteinase (MMP) substrate, a cell penetrating peptide (CPP), and 6-maleimidocaproyl amide derivative of doxorubicin (Dox). Rationale for this design is that this construct may be initially targeted to the tumor site by local application of mild heat. When the construct reaches tumor site, it is cleaved by MMP, releasing CPP conjugated Dox, which is able to more efficiently infiltrate tumor tissues and penetrate cancer cell membranes. This strategy shows up to 4-fold increase in cell penetration up to four times and results more cell death in breast cancer cells than the ELP-doxorubicin complex. Even in doxorubicin-resistant cancer cells (NCI/ADR and MES/ADR), ELP-released, cell-penetrating doxorubicin demonstrated better membrane penetration (two fold), leading to at least twice killing of the resistant cancer cells than ELP-Dox and free Dox. Citation Format: Jung Su Ryu, Drazen Raucher. Cell-penetrating doxorubicin released from Elastin-like polypeptide kills doxorubicin-resistant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5129. doi:10.1158/1538-7445.AM2017-5129
Abstract 1957: Molecular pathogenesis and drug synergism in a zebrafish model of high risk neuroblastoma
Authors: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Hillary M. Layden, A. Thomas Look
Journal: Cancer Research (2017)

Abstract We have developed a transgenic zebrafish model that overexpresses MYCN and harbors loss-of-function mutations of the nf1 tumor suppressor. In this model, loss of nf1 leads to aberrant activation of RAS-MAPK signaling, promoting both increased tumor cell survival and rapid tumor cell proliferation. These neuroblastomas are very aggressive in that almost all of the fish develop neuroblastoma by 3 weeks of age. Three-week old juvenile fish are very small, making it feasible to test the effectiveness of many drugs and drug combinations in vivo for activity against the primary tumors. We demonstrate these advantages of the model by showing marked synergistic anti-tumor effects of a MEK inhibitor (trametinib) and a retinoid (isotretinoin) in vivo at several different dosage combinations by in vivo isobologram analysis. Thus, inhibition of RAS-MAPK signaling can significantly improve the treatment of this very aggressive form of neuroblastoma when it is combined with the inhibition of other key pathways. Because of the very high penetrance and rapid onset of neuroblastoma in our nf1-deficient, MYCN-transgenic zebrafish model, it is one of the only model systems in which extensive analysis of the synergistic activity of two or more drugs can be evaluated in primary tumors in vivo. This capability is especially valuable given that mutations causing RAS-MAPK pathway hyperactivation have been shown to arise frequently at the time of relapse of childhood neuroblastomas, indicating the need to eliminate these mutated tumor cells as a component of the primary treatment. Note: This abstract was not presented at the meeting. Citation Format: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Hillary M. Layden, A. Thomas Look. Molecular pathogenesis and drug synergism in a zebrafish model of high risk 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 1957. doi:10.1158/1538-7445.AM2017-1957
Abstract 3437: Targeting microRNA-143 in glioblastoma <i>in vivo</i> increases tumor growth
Authors: Eunice Lozada-Delgado, Fatma Valiyeva, Maria Marcos, Pablo Vivas
Journal: Cancer Research (2017)

Abstract The purpose of this study is to assess the biological role of the microRNA-143 (miR-143) in Glioblastoma multiforme (GBM). GBM is the most common and lethal of all brain tumors. In the United States, the incidence of GBM is about 17% of all primary brain tumors and about 60-75% of all Astrocytomas (American Brain Tumor Association, 2014). The standard therapy is surgical tumor removal followed by chemotherapy and radiotherapy. However, many patients recur after treatment and the median survival rate for GBM has remained 15 months for the past 20 years. Thus, novel therapies for GBM treatment are urgently necessary. MicroRNAs (miRNAs) are a class of small non-coding RNAs (18-22 nucleotides in length) that regulate gene expression at the post-transcriptional level. MiRNAs bind to the 3’-untranslate region (UTR) of messenger RNAs (mRNAs) and regulate protein synthesis. Several deregulated miRNAs have been identified in all cancer types including GBM. In this study we aim to thoroughly uncover the role of miR-143 by using GBM cell lines, mouse models and patient samples. Total RNA was isolated from FFPE samples from brain tumor patients. TaqMan-based Real-time PCR showed that the relative expression of miR-143 was higher in GBM patients compared to control individuals, and with paired surrounding non-cancerous tissue. Furthermore, GBM cells transiently transfected with a miR-143 oligonucleotide inhibitor showed reduced cell proliferation (68.5%) (clonogenicity assay), increased apoptosis and cell cycle arrest of GBM cells in the S phase (Flow cytometry and Western blots). In vivo studies using primary GBM cells injected in the flank of nude mice showed that repeated doses of miR-143-inhibitor liposomal formulation increased the tumor size compared with control mice. These contradictory results could be due to effects of the microenvironment where the tumor is growing. Further studies will be made using intracranial injections in an orthotopic xenograft mouse model to confirm this hypothesis. Western blot analysis and luciferase reporter assays are also underway to identify novel miR-143 target genes in GBM cells. This research project is being supported by: PRCTRC: NCRR (U54 RR 026139-01A1), NIMHD (8U54 MD 007587-03), and RCMI: MBRS-RISE, NCRR (2G12-RR003051) and NIMHD (8G12-MD007600) from the NIH. Citation Format: Eunice Lozada-Delgado, Fatma Valiyeva, Maria Marcos, Pablo Vivas. Targeting microRNA-143 in glioblastoma in vivo increases tumor growth [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 3437. doi:10.1158/1538-7445.AM2017-3437