bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2018: Elucidating the therapeutic potential of midbrain pathways that impact breast cancer
Authors: Chandra Madeline , Lee John , Sheets Patrick L. , Prosperi Jenifer R. 
Published: August 2015

Abstract
Most chemotherapeutic agents for breast cancer have variable efficacy and produce unwanted side effects. While much focus is placed on dissecting the molecular mechanisms contributing to tumor development, the potential role of the brain in regulating tumor progression has not been described in detail. Previous evidence has shown that midbrain activity affects tumor growth and progression. Stimulation of the midbrain periaqueductal grey (PAG) increases metastasis in rats injected with Walker-256 carcinosarcoma cells, and the growth of prolactin-dependent mammary tumors. These findings suggest midbrain pathways play a prominent role in tumorigenesis. These studies, however, did not address the therapeutic potential of blocking PAG output for slowing tumor progression. Therefore, we are studying the mechanisms regulating midbrain-induced tumorigenesis and the therapeutic potential of altering midbrain activity to reduce metastatic activity and tumor growth.
A common challenge in neuroscience has been identifying and manipulating specific neuronal populations in the brain. However, significant advances have been made in the field of optogenetics, the integration of optics and genetics, which allows precise control of specific neural pathways in vivo using light. Optogenetics is gaining considerable clinical interest as a novel strategy for treating human neurological disorders due to success observed in rodent and non-primate human models. Therefore, optogenetic alteration of PAG activity for treating breast cancer is plausible. Non-pharmacological, therapeutic strategies aimed at manipulating circuit activity to treat mood and anxiety disorders are already creating enthusiasm. Given that many of these strategies likely impact PAG activity, there is great potential for manipulating the same pathways to treat breast cancer. Before these types of novel strategies can be implemented, we must first delineate the biology of these circuits and their therapeutic potential in animal models of cancer.
Thus far, we have identified that muscimol inhibition of PAG activity decreases breast cancer progression in a transgenic mouse model. We are continuing to investigate the distinct input/output mechanisms of the PAG that could be modified to treat breast cancer. Future studies have the potential to reveal novel avenues for targeting and preventing the development of breast cancer via the manipulability of specific neural pathways.
Note: This abstract was not presented at the meeting.
Citation Format: Madeline Chandra, John Lee, Patrick L. Sheets, Jenifer R. Prosperi. Elucidating the therapeutic potential of midbrain pathways that impact breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2018. doi:10.1158/1538-7445.AM2015-2018
Abstract 2030: FRK regulates glioma cell progression by promoting N-cadherin/β-catenin complex formation
Authors: Shi Qiong , Song Xu , Yan Haoping , Wang Jun , Zhang Weijian , Hu Jinxia , Zhou Xiuping , Yu Rutong 
Published: August 2015

Abstract
Fyn-related kinase (FRK), a member of Src-related tyrosine kinases, is recently reported to function as a potent tumor suppressor in several cancer types. Our previous studies has also shown that FRK over-expression inhibited the migration/invasion, proliferation and promoted apoptosis of glioma cells. However, the mechanism of FRK on glioma cell migration/invasion, proliferation and apoptosis is still not clear. In this study, we found that FRK over-expression increased the protein level of N-cadherin, but not that of E-cadherin. Meanwhile, FRK over-expression promoted β-catenin translocation to the plasma membrane, where it formed complex with N-cadherin, while inhibited β-catenin translocation to the nucleus. In addition, down-regulation of N-cadherin by siRNA promoted the migration/ invasion proliferation and inhibited apoptosis of glioma U251 and U87 cells. Interestingly, N-cadherin down-regulation abolished the effect of FRK on glioma cell migration/invasion, proliferation and apoptosis. In summary, these results indicate that FRK regulates glioma cell progression by promoting N-cadherin/β-catenin complex formation.
Citation Format: Qiong Shi, Xu Song, Haoping Yan, Jun Wang, Weijian Zhang, Jinxia Hu, Xiuping Zhou, Rutong Yu. FRK regulates glioma cell progression by promoting N-cadherin/β-catenin complex formation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2030. doi:10.1158/1538-7445.AM2015-2030
Abstract 204: Single-molecule localization microscopy analysis of a cancer metastasis-specific miRNA on the nanoscale
Authors: Abba Mohammed , Oleksiuk Olga , Tezcan Kerem , Schaufler Wladimir , Bestvater Felix , Altevogt Peter , Hafner Mathias , Cremer Christoph , Allgayer Heike 
Published: August 2015

Abstract
We propose a novel approach for the detection of small non-coding RNAs in cells by Single Molecule Localization Microscopy (SMLM). We describe a modified and upgraded SMLM-setup and apply this instrument in a first proof-of-principle concept to human cancer cell lines. Our method is able to visualize single microRNA molecules in fixed cells with a localization accuracy of 10-15 nm, is able to quantify numbers and analyse clustering and localization in particular subcellular sites, including exosomes. We compared metastatic-site derived and primary site derived human adenocarcinoma cultured colorectal cancer (CRC) cells, and (as a proof of principle) evaluated the metastatically relevant miR-31 as a first example. We observed that the subcellular distribution of miR-31 molecules in all cell lines was very heterogeneous with the largest subpopulation of optically acquired low-metastatic cells characterized by a low number of miR-31 molecules, as opposed to a significantly higher number in the majority of the highly metastatic cells.
Citation Format: Mohammed Abba, Olga Oleksiuk, Kerem Tezcan, Wladimir Schaufler, Felix Bestvater, Peter Altevogt, Mathias Hafner, Christoph Cremer, Heike Allgayer. Single-molecule localization microscopy analysis of a cancer metastasis-specific miRNA on the nanoscale. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 204. doi:10.1158/1538-7445.AM2015-204
Abstract 2041: Quantitative phosphoproteomic analysis of EphA2 signaling in PC-3 prostate cancer cells
Authors: Offenhäuser Carolin , Dave Keyur A. , Jayakody Buddhika A. , Gorman Jeffrey J. , Boyd Andrew W. 
Published: August 2015

Abstract
The receptor tyrosine kinase EphA2 is frequently upregulated in cancer, where it plays an intriguing dichotomous role that may lend itself to therapeutic intervention. However, much remains to be understood about how ephrin-mediated activation of EphA2 signaling can reverse its tumour-promoting ligand-independent effects and instead inhibit migration and invasion. We used quantitative phosphoproteomics to analyze EphA2 signaling in PC-3 prostate cancer cells with the aim to further elucidate its downstream signaling and pinpoint phosphorylation-dependent cellular processes that may explain its dichotomous role. Stable isotope labeling by amino acids in cell culture (SILAC) combined with liquid chromatography-coupled mass spectrometry (LC-MS/MS) was used to quantify changes in relative phosphosite abundance in response to EphA2 activation. We identified 113 significantly regulated phosphosites comprising 73 phosphoproteins, including many novel and several previously described downstream effector proteins of EphA2 signaling. More than two thirds of the regulated phosphosites showed reduced phosphorylation in response to EphA2 activation. This is consistent with EphA2 activation inhibiting oncogenic signaling pathways, including Akt and ERK-MAPK signaling. Protein association analysis using the STRING database showed that a large proportion of these differentially regulated proteins are downstream targets of Akt and ERK-MAPK, respectively. Gene ontology enrichment analysis found our dataset to be strongly enriched in proteins associated with the cytoskeleton and its regulation. Overall, our data suggest that diminished phosphorylation of cytoskeletal regulators downstream of Akt and ERK-MAPK signaling may be a major mechanism by which stimulation of EphA2 can alter cell morphology and inhibit cell motility.
Citation Format: Carolin Offenhäuser, Keyur A. Dave, Buddhika A. Jayakody, Jeffrey J. Gorman, Andrew W. Boyd. Quantitative phosphoproteomic analysis of EphA2 signaling in PC-3 prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2041. doi:10.1158/1538-7445.AM2015-2041
Abstract 2050: Persistent STAT3 signaling contributes to the resistance of anti cancer drugs doxorubicin and cisplatin, and MEK inhibitor AZD6244 in human sarcoma cells
Authors: Wu Xiaojuan , Xiao Hui , Li Chenglong , Lin Jiayuh 
Published: August 2015

Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway is activated in response to cytokines and growth factors. Persistently activated STAT3 are frequently detected in many types of human cancers and are believed to play an important role in their oncogenesis. Stat3 has been classified as a proto-oncogene because activated STAT3 can mediate oncogenic transformation in cultured cells and tumor formation in nude mice. We previously demonstrated that persistently activated STAT3 is frequently detected in human sarcoma such as rhabdomyosarcoma. To further examine the role of persistent TAT3 signaling plays in rhabdomyosarcoma, we used genetic approaches to either knock-down the expression of STAT3 using short hairpin RNA (ShRNA) or expressed constitutive active STAT3 protein. Knock-down the expression of STAT3 in rhabdomyosarcoma cells that express persistent STAT3 signaling, reduced the cell viability and sensitized cells to anti-cancer drugs doxorubicin and cisplatin. On the other hand, expression of constitutive active STAT3 protein in rhabdomyosarcoma cell lines lacking persistent STAT3 signaling decreased the sensitivity of those cells to doxorubicin and cisplatin. Furthermore, a MEK inhibitor, AZD6244 that is being tested in human cancer clinical trials unexpectedly induced STAT3 phosphorylation suggesting inducing of STAT3 may induce intrinsic resistance to MEK inhibitor. Accordingly, knock down of STAT3 sensitize sarcoma cells to MEK inhibitor treatments. To further translate our finding to potential cancer therapy, we tested a small molecular STAT3-selective inhibitor LY5 in sarcoma cells expressing persistent STAT3 signaling. Our data demonstrated that LY5 inhibited STAT3 phosphorylation, STAT3 DNA binding activity, and the migration of sarcoma cells. In addition, the combination of LY5 with anti-cancer drugs doxorubicin and cisplatin and the MEK inhibitor, AZD6244 also shown stronger inhibitory effects than single agent alone. In summary, our results using both genetic and small molecule approaches demonstrated that persistent STAT3 signaling contributes to the resistance of anti-cancer drugs doxorubicin and cisplatin, and MEK inhibitor in human sarcoma cells. They also implicated a potential cancer therapy strategy with the combination of STAT3 inhibitor with doxorubicin, cisplatin, and MEK inhibitor in sarcoma cells expressing persistent STAT3 signaling.
Citation Format: Xiaojuan Wu, Hui Xiao, Chenglong Li, Jiayuh Lin. Persistent STAT3 signaling contributes to the resistance of anti cancer drugs doxorubicin and cisplatin, and MEK inhibitor AZD6244 in human sarcoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2050. doi:10.1158/1538-7445.AM2015-2050
Abstract 2060: DUSP6 phosphatase as a tumor suppressor in non-small cell lung cancer
Authors: Perona Rosario , Moncho-Amor Veronica , Ibanez de Caceres Inmaculada , Pintado-Berninches Laura , Martin Ester , Quintanilla Miguel , Cortes-Sempere María , Sastre Leandro , Belda-Iniesta Cristobal 
Published: August 2015

Abstract
DUSP6/MKP3 a Map Kinase phosphatase involved in dephosphorylation and inactivation of ERK1/2 is a key gene whose expression in NSCLC is regulated by the DUSP1 Map Kinase phosphatase. Here we show that DUSP6 plays a major role in the regulation of cell migration, motility and tumor growth. We have found upregulation in the expression of several genes involved in Epidermal to mesenchimal transition in NSCLC-DUSP6 depleted cells. Furthermore ERK5 expression and phosphorylation, but not ERK1/2 is greatly enhanced in these cells. Finally the data obtained in RNAseq studies carried out in DUSP6 depleted cells identified several genes such as VAV3, RUNXR2, LEF1, FGFR2 whose expression is upregulated in these cells and affecting cellular functions such as integrin mediated cell adhesion and focal adhesion supporting the changes in cell adhesion and motility observed in DUSP6 depleted cells. TGFβ pathway is activated in these cells as we have observed phosphorylation of SMAD3 and consequently inhibition of TGFβ reduces the expression of EMT genes. Finally in silico studies from Gene Expression Omnibus and The Cancer Genome Atlas databases indicates that those NSCLC patients with low expression of DUSP6 are those with the worst prognosis.
Citation Format: Rosario Perona, Veronica Moncho-Amor, Inmaculada Ibanez de Caceres, Laura Pintado-Berninches, Ester Martin, Miguel Quintanilla, María Cortes-Sempere, Leandro Sastre, Cristobal Belda-Iniesta. DUSP6 phosphatase as a tumor suppressor in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2060. doi:10.1158/1538-7445.AM2015-2060
Abstract 2061: CHIP functions as tumor suppressor in prostate cancer through suppression of ROS-inflammasome in a chaperone-dependent mechanism
Authors: Said Neveen A. , Larner James 
Published: August 2015

Abstract
Prostate Cancer (PCa) is a disease closely associated with aging. Normal aging is driven by oxidative stress, resulting in accumulation of markers of protein and lipid/phospholipid damage with subsequent activation of inflammatory/oncogenic transcription factors NFκB and AP-1. Indeed, the tumor milieu characterized by ROS signaling, and NFκB- and AP1-activation is thought to be important in fueling cancer progression and metastasis. CHIP is a U-box-type E3-ubiquitin ligase that exerts a protective role against oxidative stress by targeting damaged proteins for proteasomal degradation to maintain tissue homeostasis. CHIP induces ubiquitylation and degradation of substrates, including oncogenes and oxidatively damaged, and misfolded proteins. We hypothesized that CHIP suppresses prostate tumor progression by inhibiting ROS generation and downstream oncogenic pathways. CHIP depletion in PCa cells significantly increased their anchorage-independent growth, migration and invasiveness. PCa cells depleted of CHIP exhibited increased ROS generation (H2O2) and expression of markers of oxidative stress 8-isoprostane, NOQ1, NNMT and sulfiredoxin with subsequent activation NFκB and AP-1. The increased activation of NFκB and AP-1 in CHIP-depleted cells was ROS-induced as it was inhibited by N-acetyl cysteine (NAC) or knockdown of NOQ1. Pharmacologic inhibition of Hsp90 inhibited basal and ROS-induced NFκB and AP-1 activation as well as their invasive phenotype suggesting that the effect of CHIP is in part chaperone-dependent. Furthermore, in subcutaneous and orthotopic xenografts, PCa cells depleted of CHIP exhibited significantly accelerated growth compared to controls. Molecular characterization of CHIP-depleted tumors revealed significantly increased proliferation, increased oxidative stress and inflammation with increased nuclear localization of NFκB and AP-1. Collectively, our data suggest a novel tumor suppressor role of CHIP in PCa mediated through inhibition of ROS-induced inflammation.
Citation Format: Neveen A. Said, James Larner. CHIP functions as tumor suppressor in prostate cancer through suppression of ROS-inflammasome in a chaperone-dependent mechanism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2061. doi:10.1158/1538-7445.AM2015-2061
Abstract 2063: A novel ELAVL1-TYK2 fusion protein drives STAT3/5 activation and PIM-1 expression, survival and growth in the MOLM-16 acute myeloid leukemia cell line
Authors: McEachern Kristen , Keeton Erika , Dillman Keith , Ye Minwei , Stengel Chloe , Chen Huawei , Wang Suping , Grosskurth Shaun , Gale Rosemary E. , Linch David C. , Khwaja Asim , Lai Zhongwu , Huszar Dennis 
Published: August 2015

Abstract
Pim kinases are upregulated in leukemias and lymphomas and mediate cell growth and survival. Acute myeloid leukemia cell lines sensitive to the pan-Pim kinase inhibitor AZD1208 showed elevated pSTAT5 and Pim-1 expression that correlated with known tyrosine kinase mutations. However, one of the most sensitive lines, MOLM-16, lacked a reported driver mutation. RNA transcriptome sequencing identified a novel fusion gene comprised of the TYK2 kinase domain fused to the N-terminus of the RNA binding protein ELAVL1/HuR. The genes are co-localized within ∼2 MB on the short arm of chromosome 19, at position 13.2. The fusion results in loss of the Tyk2 pseudokinase domain, which negatively regulates kinase activity, suggesting a gain of function genetic alteration. Tyk2 was highly expressed and found to be amplified in MOLM-16 cells, with a higher degree of amplification of the exons encoding the kinase domain. Knockdown experiments demonstrated that down-regulation of the fusion gene, but not of the wild type ELAVL1 or TYK2 transcripts, resulted in suppression of STAT3/5 phosphorylation, Pim1 levels, and proliferation. Conversely, expression of the ELAVL1-TYK2 fusion protein in FDCP1 cells was shown to confer IL-3 independent growth. The fusion was not identified in screening of ∼200 AML patient samples or through analysis of TCGA data suggesting that it occurs at a low frequency, but interestingly NPM1-Tyk2 fusions have recently been described in cutaneous CD30-positive lymphoproliferative disorders (Velusamy et al. Blood 2014).
Citation Format: Kristen McEachern, Erika Keeton, Keith Dillman, Minwei Ye, Chloe Stengel, Huawei Chen, Suping Wang, Shaun Grosskurth, Rosemary E. Gale, David C. Linch, Asim Khwaja, Zhongwu Lai, Dennis Huszar. A novel ELAVL1-TYK2 fusion protein drives STAT3/5 activation and PIM-1 expression, survival and growth in the MOLM-16 acute myeloid leukemia cell line. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2063. doi:10.1158/1538-7445.AM2015-2063
Abstract 2071: Disruption of TGFβ-mediated tumor suppression in a Tpl2 model of cutaneous squamous cell carcinoma
Authors: Falkenberg Lauren , Gwilliam J. Curtis , Decicco-Skinner Katie L. 
Published: August 2015

Abstract
Skin cancer is the most common form of cancer in the United States, with an estimated two million cases diagnosed annually, and incidence continues to increase. Tpl2 (Map3k8) is a serine threonine protein kinase in the mitogen-activated protein kinase (MAPK) signal transduction cascade. Previous studies have shown that Tpl2-/- mice develop significantly more skin tumors than matched wildtype controls and keratinocytes harvested from Tpl2-/- mice display multiple biomarkers for cutaneous squamous cell carcinoma (cSCC.) We have previously established that crosstalk between Tpl2-/- keratinocytes and dermal fibroblasts contributes to the transformative potential of our model, and we hypothesized that one of the possible mechanisms driving this transformation was dysregulation of the TGFβ pathway, which plays multiple roles in carcinogenesis but is known to have an anti-proliferative function in noncancerous cells. Using various techniques, including real-time polymerase chain reaction, matrix-metalloproteinase zymography, in vitro angiogenesis assays, and immunoblotting, we saw that both Tpl2-/- keratinocytes and dermal fibroblasts secreted less TGFβ and displayed significant dysregulation of multiple components of the TGFβ pathway. In summary, our studies demonstrate that loss of Tpl2 results in disruption of TGFβ-mediated tumor suppression, and that disruption is in part caused by abnormal signalling from fibroblasts in the tumor microenvironment.
Citation Format: Lauren Falkenberg, J. Curtis Gwilliam, Katie L. Decicco-Skinner. Disruption of TGFβ-mediated tumor suppression in a Tpl2 model of cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2071. doi:10.1158/1538-7445.AM2015-2071