bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1088: Defining bone metastatic potential of Abi1 CRISPR prostate cancer cell lines
Authors: Nappi Alexander , Post Dawn , Das Disharee , Joshi Ishita , Oest Megan , Bratslavsky Gennady , Kotula Leszek 
Published: August 2018

Abstract
Prostate cancer is the second most common cancer in American men, and it is the third leading cause of cancer-related deaths in American men. Distant stage and metastatic disease is often treated with androgen-deprivation therapy (ADT); however, this treatment ultimately fails, leading to castration-resistant prostate cancer (CRPC). This further emphasizes the need for better therapeutic targets. Our work focuses on understanding the role of the Abi1 gene in prostate cancer tumor progression. Our current in vitro data demonstrate an invasive phenotype with our CRISPR-mediated Abi1 knockout (KO) cell lines. In total, using CRISPR-mediated technology we have generated four Abi1 gene KO cell lines, PC-3, DU145, LnCaP, and RWPE-1. Importantly, the androgen-dependent cell line, LNCaP, demonstrated upregulation of Abi1 to the androgen receptor stimulation and the opposite response to the receptor inhibition upon treatment with enzalutamide. These data indicated that low Abi1 level could be induced by ADT therapies and are consistent with our previous observation of low Abi1/WAVE complex in prostate tumor samples. To learn more about this mechanism, we set out to investigate the role of Abi1 in castrated mice. The overall goal of the experiment is to compare the ability of cells lacking the Abi1 gene to engraft in bone under androgen deprivation condition and compare it to the control cells and examine any change in the engraftment phenotype. It is hoped that this research will lead to better understanding of the Abi1/WAVE complex role in CRPC.
Supported by NCI R01 CA16101.
Citation Format: Alexander Nappi, Dawn Post, Disharee Das, Ishita Joshi, Megan Oest, Gennady Bratslavsky, Leszek Kotula. Defining bone metastatic potential of Abi1 CRISPR prostate cancer cell lines [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 1088.
Abstract 1090: The role of connexin43 in prostate cancer motility
Authors: Aloliqi Abdulaziz A. 
Published: August 2018

Abstract
Prostate cancer (PC) is one of the most common male cancers in United States. PC lethality is due to metastatic growth, when cancer cells move from the primary tumor site to a secondary site. A key step in metastsis is the acquisition of motility. Connexins (Cx) play a major role in cell-cell communication and growing evidence demonstrates their contribution to cell motility. Cx43 is up-regulated in cultured PC3 metastatic prostate cancer cells. To understand the role of Cx43 in migration we asked whether silencing Cx43 would decrease PC3 cell migration. Using cells in which short interfering RNA (sh-RNA) silenced Cx43 mRNA, we showed that silencing Cx43 decreased motility of sh-Cx43 PC3 cells in Boyden chamber assays. To confirm these results in another biological system, we performed cellular wound healing assays. Silencing Cx43 decreased motility of PC3 cells reducing movement to wounded area, leaving more area open in the Cx43 inhibited cell lines. The wound healing assay showed that knockdown Cx43 altered directional movement, velocity and distance. These results supported those of our Boyden assays showing that loss of Cx43 decreases the migratory ability of PC3. Conversely, the overexpression of Cx43 in LNCaP cells, non-migratory prostate cancer cells that lack Cx43 expression, increased their motility. A comparison of cell lines engineered to overexpress or to silence Cx43 confirms the importance of Cx43 in the motility of prostate cancer cells in vitro. Although the mechanism whereby Cx43 regulates motility is still unclear, our preliminary data revealed that Cx43 co-immunoprecipitated with N-cadherin, suggesting that they form a complex in PC3 cells. Cell fractionation studies of PC3 control cells showed that N-cadherin was located in the cell membrane and not detected free in the cytoplasm, but in sh-Cx43 PC3 cells that lack Cx43, the distribution of N-cadherin protein was altered and significant levels of N-cadherin were also detected in cytoplasmic fractions. Whether changes in N-cadherin distribution is a direct or indirect result of loss of Cx43 in sh-Cx43 PC3 cells, is unclear. However, modulation of Cx43 levels in prostate cancer cells does alter motility and N-cadherin distribution. These results indicate that Cx43 and N-cadherin are in close association in PC3 cells and their interaction may play an important role in prostate cancer cell motility. A better understanding of the requirements of migratory PC cells may lead to more effective targeting of key steps in PC progression to lethal metastatic disease.
Citation Format: Abdulaziz A. Aloliqi. The role of connexin43 in prostate cancer motility [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 1090.
Abstract 1093: Epithelial-to-mesenchymal transition conveys resistance to restrictive growth conditions through increased autophagic flux
Authors: Zhao Lei , Nauseef Jones , Buchakjian Marisa , Barnes Matthew , Henry Michael 
Published: August 2018

Abstract
Tumor progression requires cancer cells to adapt to varying microenvironments both in the primary tumor and in metastatic end organs. Metastasis is enhanced by epithelial-to-mesenchymal transition (EMT), which facilitates invasiveness and confers resistance to local stresses, such as hypoxia and nutrient limitation, although EMT is not necessarily required for these processes. Among these stressors, growth-factor (GF) deprivation may induce or select for cells that bear the hallmarks of EMT (EMT-like cells). The mechanisms by which EMT-like cells survive GF deprivation (restrictive growth conditions), which may occur when metastatic cancer cells are removed from GFs resident in the primary tumor microenvironment, remain largely uncertain. Herein we show that EMT confers upon cells the ability to maintain proliferative potential, following extended serum deprivation. We found that EMT-like prostate cancer cells (TEM 4-18) demonstrate elevated survival and reduced senescence compared to their more epithelial counterparts (PC-3E) in both short- and long-term exposure to serum withdrawal. In addition, resistance to anchorage-dependent growth-induced apoptosis (Anoikis) due to elevated autophagy is also evident in EMT-like cells. Forced expression of snail1 conferred survival advantages to PC-3 cells. Conversely, CRISPR-mediated knockout of Zeb1 reversed EMT status in TEM4-18 cells and survival advantage in restrictive growth conditions. We found that EMT-like cells exhibit elevated autophagic flux. Genetic interference with autophagy in EMT-like cells reversed their survival advantage and increased senescence in restrictive growth conditions as well as anoikis resistance. Our results suggest that the metastatic capabilities of EMT-like cells depend not only on their established invasive characteristics, but also on increased autophagy tied to the EMT-like state, and its role in surviving restrictive growth conditions.
Citation Format: Lei Zhao, Jones Nauseef, Marisa Buchakjian, Matthew Barnes, Michael Henry. Epithelial-to-mesenchymal transition conveys resistance to restrictive growth conditions through increased autophagic flux [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 1093.
Abstract 1094: A role for olfactory-like chemosensory signaling in prostate cancer metastasis
Authors: Lam Hong , Zhu Wanqu , Wang Hailun , Luo Jun , Zheng Qizhi , Valkenburg Ken , Hurley Paula , Pluznick Jennifer L. , Tran Phuoc T. , Marzo Angelo M. De , Isaacs William B. , Pienta Kenneth J. , An Steven S. 
Published: August 2018

Abstract
Odorant sensing G protein-coupled receptors (ORs) are the largest signaling family encoded by the mammalian genome. Historical understanding suggests these specialized receptors are only expressed on sensory neurons in the main olfactory epithelium and respond to external ligands involved in smell perception. More recently, olfactory-like chemosensory signaling has been found in a variety of non-sensory tissues and shown to be evoked by endogenous metabolic byproducts of anaerobic bacteria and hypoxia. Here we screened the full complement of ORs in the prostate and studied their expression and function in the context of metastatic-invasion of prostate cancer (PCa). In the germline of men with lethal PCa, we detected a large number of nonsynonymous coding changes in ~400 different OR genes including specific missense and loss-of-function mutations that are present in higher rates than would be predicted. RNA-Seq of clinical prostate samples showed higher OR51E2 expression in localized PCa than normal prostate. Most striking, we detected a low abundance of the OR51E2 transcript in PCa metastases to the bone relative to localized. Similarly, we found a marked reduction of OR51E2 expression in PCa cell lines that were derived from bone metastases, or those that had undergone an epithelial-mesenchymal transition (EMT) phenotype through co-culture with IL4-treated CD14+ monocytes. Using mouse models of PCa metastasis, we confirmed the overexpression of OR51E2 in localized tumors generated by subcutaneous injection while observing a marked reduction in PCa cells metastatic to the bone that also demonstrated a mesenchymal cellular phenotype. Together these findings establish, for the first time, a novel role for ‘sensory GPCRs' in PCa progression to metastasis.
Grant supports: The Johns Hopkins Discovery Award; The Johns Hopkins Catalyst Award; Maryland Cigarette Restitution Fund
Citation Format: Hong Lam, Wanqu Zhu, Hailun Wang, Jun Luo, Qizhi Zheng, Ken Valkenburg, Paula Hurley, Jennifer L. Pluznick, Phuoc T. Tran, Angelo M. De Marzo, William B. Isaacs, Kenneth J. Pienta, Steven S. An. A role for olfactory-like chemosensory signaling in 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 1094.
Abstract 1095: Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) regulates mitochondrial dynamics, EMT and angiogenesis in progression of prostate cancer
Authors: Dheeraj Arpit , Tailor Dhanir , Deep Gagan , Singh Rana P. 
Published: August 2018

Abstract
Prostate cancer (PCa) is a major epithelial cancer among men and with the second highest incidence rate, worldwide. The high ratio of IGF-1/IGFBP-3 correlates with increased risk of many cancers including prostate cancer. In present study, we have evaluated the role of IGFBP-3 and effect of fisetin, a phytochemical, active constituent of strawberry, apple etc. in the progression of prostate cancer. The exogenous expression of IGFBP-3 moderately decreased the cell growth and it further decreased with addition of fisetin in DU145 and LNCaP cells. The restoration of IGFBP-3 in DU145 cells inhibited the clonogenic potential which is further decreased with fisetin treatment. Increased ROS content was observed in IGFBP-3 overexpression condition, however fisetin treatment reversed the ROS content in DU145, shows antioxidant behaviour. Morphological examination of mitochondria revealed that IGFBP-3 overexpression destabilizes the mitochondrial dynamics by reduction in active DRP1 level which has been reversed by fisetin treatment. We evaluated the effect on mitochondrial mass which was decreased in IGFBP-3 overexpressing DU145 cells which further decreased with addition of fisetin at 12 and 24 h. IGFBP-3 overexpression decreased the migratory potential of DU145 cells under normoxic conditions and under hypoxic condition it increased the migration of DU145 cells. Furthermore, IGFBP-3 overexpression decreased the VEGF expression as compared to vector control which can inhibit the expansion of tumor cells. Under the hypoxic conditions (1% oxygen), cells showed increased levels of IGFBP-3 when compared to normoxic conditions (21% Oxygen) in time dependent manner. The down-regulation of IGFBP-3 in PC3 cells, increased the expression of E-cadherin, a biomarker of epithelial to mesenchymal transition. The wound scratch assay showed the pro-migratory role of IGFBP-3 in PC3 cells and treatment with fisetin inhibited the migration of these cells under the hypoxic condition. The knockdown of IGFBP3 resulted in the decreased invasive potential of PC3 in comparison to cells in hypoxic state. Together with these observation, IGFBP-3 have shown biphasic character depending on normoxic and hypoxic condition in controlling the prostate cancer progression.
Citation Format: Arpit Dheeraj, Dhanir Tailor, Gagan Deep, Rana P. Singh. Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) regulates mitochondrial dynamics, EMT and angiogenesis in progression of prostate cancer [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 1095.
Abstract 1098: Innate immune response to primary breast cancer prevents metastasis-initiating cell colonization
Authors: Castano Zafira 
Published: August 2018

Abstract
Current lack of insight into mechanisms governing breast cancer metastasis has precluded development of curative therapies. Previous reports, including our own, have demonstrated that metastatic success is due to tumor cell intrinsic properties as well as microenvironmental and systemic factors (Castano, et al., Cancer Discovery, 2013). The goal of our current study was to determine whether metastasis initiating cells (MIC), i.e., cells enriched for metastatic capacity, also rely on systemic cues. Using a preclinical model of the early phases of breast cancer metastasis, when cells are disseminated in the presence of the primary tumor (McAllister, et al., Cell 2008), we were surprised to find that certain primary tumors inhibit progression of disseminated MICs into overt tumors. In the presence of the primary tumor, MICs were maintained in a Zeb1hi/CDH1lo state and were less proliferative and poorly differentiated relative to those that formed in the absence of the primary tumor. We established that the primary tumor induces mobilization of IL1beta-expressing innate immune cells that are recruited to sites where MICs reside. At those sites, signaling via the IL1 receptor maintains MICs in the Zeb1hi/CDH1lo state, thus promoting disease indolence. Confirming our xenograft results, we established that expression of IL1beta in patient tumors is associated with metastasis free survival. Collectively, these data highlight the profound impact a primary tumor can exert on metastasizing cells - in this case, by altering the systemic environment to the detriment of secondary tumor growth-. Moreover, our data highlight a central role for IL1 pathway in modulating tumor cell plasticity and suggest it may provide a novel avenue for targeting recurrent disease.
Citation Format: Zafira Castano. Innate immune response to primary breast cancer prevents metastasis-initiating cell colonization [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 1098.
Abstract 1109: S100A10 contributes to cancer stemness, invasion and metastasis of head and neck cancer cells
Authors: Tanaka Nobuyukit , Nishikawaji Taketo , Ogama Naoko 
Published: August 2018

Abstract
Head and neck cancer is one of the most common cancers worldwide, and an innovating therapy is awaited. We attempted to identify proteins associated with cancer stem cell phenotypes, and found an EF-hand protein S100A10 is highly expressed in the stem cell population. Together with its binding partner, Annexin-A2, S100A10 regulates a spectrum of dynamic membrane-related events, such as actin cytoskeleton control, vesicle formation and intercellular interaction. Immunohistochemical analysis using clinical head and neck cancer specimens showed that elevated S100A10 expression is typically present in the invasion front of tumors, and S100A10-high cases were associated with poor prognosis. S100A10 knockdown and knockout resulted in significant reduction of cell migration and invasion in vitro. Cell movement was slowed down by S100A10 knockdown. Accordingly, in vivo tumor formation was impaired by S100A10 depletion. Cell cycle progression was delayed by the depletion, suggesting its potential role in proliferation controls. These results suggest that S100A10 has a significant role in head and neck cancer cell proliferation and invasion.
Citation Format: Nobuyukit Tanaka, Taketo Nishikawaji, Naoko Ogama. S100A10 contributes to cancer stemness, invasion and metastasis of head and neck cancer cells [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 1109.
Abstract 1117: Norrin signaling is protumorigenic in glioblastoma progression
Authors: Elsehemy Ahmed A. , Selvadurai Hayden , Rowland Katherine , Dirks Peter , Wallace Valerie 
Published: August 2018

Abstract
Norrin signaling is protumorigenic in GBM progression
A-Introduction:
Norrin, a secreted factor encoded by the Norrie Disease Protein gene (NDP), is an atypical WNT ligand that specifically binds the FZD4 receptor and activates the canonical WNT signaling pathway in endothelial cells to regulate vascular development and barrier function in the brain. Recently, our group identified a novel tumor inhibitory function of NDP/FZD4 signaling in the endothelium in mouse models of medulloblastoma. Here we investigated the function of the NDP/FZD4 signaling axis in glioblastoma (GBM) progression.
B-Experimental approaches
GBM patients' survival data was obtained from TCGA and analyzed using the cBioportal server. Low passage mitogen expanded GBM cancer stem cell lines were established from primary tumors using standard conditions. NDP expression in experimental cell lines was modulated using lentiviral delivery of short hairpins or full length cDNA. Cell number was assessed by trypan blue cell counting, and sphere forming cell frequency was tested using extreme limited dilution assay (ELDA). For in vivo assessment of tumorigenesis, experimental and control cell lines were xenografted intracranially in NOD/SCID/Gamma (NSG) mice and symptomatic animals were euthanized and brains collected for histological analysis.
C-Results
Analysis of GBM data from TCGA showed that survival and NDP expression are negatively GBM. Gene expression analysis indicated variable expression levels of NDP/FZD4 signaling pathway components in a panel of 10 primary GBM stem cell lines. In vitro gain and loss of function studies showed that NDP promotes proliferation and sphere formation in GBM. Moreover, the effects of are recapitulated in xenografts. NDP appears to control GBM differentiation, as it affects the proportion of cycling (Ki67+) cells and the level of stemness (Sox2 levels). Finally, NDP function is independent of FZD4 and canonical Wnt signaling, indicating that it functions through an alternative pathway.
D-Conclusions Our in vitro and in vivo results indicate that Norrin might have an oncogeneic role in GBM. In addition, the effect of Norrin is FZD4- and WNT-independent. Our results indicate that targeting Norrin GBM might be a potential therapeutic approach.
Citation Format: Ahmed A. Elsehemy, Hayden Selvadurai, Katherine Rowland, Peter Dirks, Valerie Wallace. Norrin signaling is protumorigenic in glioblastoma progression [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 1117.
Abstract 1122: MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radio resistance in glioblastoma
Authors: Huang Tianzhi , Kim Chung Kwon , Alvarez Angel A. , Pangeni Rajendra P , Wan Xuechao , song xiao , shi Taiping , Yongyong Yongyong , Sastry Namratha , Horbinski Craig , Lu Songjian , Stupp Roger , Kessler John , Nishikawa Ryo , Nakano Ichiro , Sulman Erik , Lu Xinghua , James Charles David , Yin Xiao-Ming , Hu Bo , Cheng Shi-Yuan 
Published: August 2018

Abstract
Autophagy-mediated intracellular catabolism sustains the rapid growth of established tumors and tumors in response to multiple stresses including genotoxic/cytotoxic therapies. Here we identify and validate ATG4B, a key regulator that stimulates autophagic process by promoting autophagosome through reversible modification of ATG8 as a novel substrate of mammalian sterile20-like kinase (STK) 26/MST4 that is less known for its function in cellular process (none in autophagy) and unknown authentic substrates in cancer. We show that MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities suppresses autophagic process and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM tumor xenografts markedly slows tumor growth and provides significant survival benefit to animal subjects. This study not only describes a novel regulatory mechanism by which the MST4-ATG4B axis accelerates autophagic process, regulates GBM tumorigenicity, and responses to radiotherapy (RT), but also explores imminent clinical utility of combination of ATG4B inhibition with RT to suppress orthotopic GBM tumor xenografts. This study should prove generalizable to other types of cancer and have positive impacts in advancing our knowledge of cancer biology and designing new cancer treatments.
Citation Format: Tianzhi Huang, Chung Kwon Kim, Angel A. Alvarez, Rajendra P Pangeni, Xuechao Wan, xiao song, Taiping shi, Yongyong Yongyong, Namratha Sastry, Craig Horbinski, Songjian Lu, Roger Stupp, John Kessler, Ryo Nishikawa, Ichiro Nakano, Erik Sulman, Xinghua Lu, Charles David James, Xiao-Ming Yin, Bo Hu, Shi-Yuan Cheng. MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radio resistance in glioblastoma [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 1122.