bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5477: Hydrogels to study ECM-oxygen gradient interactions for sarcoma cell migration
Authors: Lewis Daniel M. , Gerecht Sharon , Eisinger-Mathason T. S. Karin 
Published: July 2017

Abstract
Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O2 depletion. Here, we report the impact of hypoxic O2 gradients and collagen fibers on sarcoma cell invasion and migration. We begun with O2 gradient measurements and found that large sarcoma mouse tumors (&gt;300 mm3) contain a severely hypoxic core [≤0.1% partial pressure of O2 (pO2)] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1–6% pO2). To analyze tumor invasion, we used O2-controllable hydrogels to recreate the physiopathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O2 gradient accurately, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Next, we have developed hypoxic hydrogels where we can control collagen fiber density and cross-linking density independently from oxygen gradients. Using this new platform we show that an increase in fiber density in conjunction with the hypoxic oxygen gradient leads to an increase in sarcoma cell migration. This increase in migration speed was also correlated with quicker stress relaxation times of the collagen gel and larger pore size. Using these platforms we are able to create a novel 3D experimental system with control over mechanical properties (crosslinking density, binding sight density, fiber density, stress relaxation time, and stiffness) independently from oxygen concentration. Overall, we show that O2 acts as a 3D physicotactic agent during sarcoma tumor invasion and that this migration is modulated by collagen fiber density and pore size, in the surrounding matrix. We propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets.
Citation Format: Daniel M. Lewis, Sharon Gerecht, T. S. Karin Eisinger-Mathason. Hydrogels to study ECM-oxygen gradient interactions for sarcoma cell migration [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 5477. doi:10.1158/1538-7445.AM2017-5477
Abstract 5492: Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and nuclear structure
Authors: Brown Markus A. 
Published: July 2017

Abstract
The organization of the genome in the nucleus is complex and dynamic. Features of the nuclear architecture, including the spatial arrangement of genomic sequences, the structure of chromatin, and the accessibility of regulatory DNA elements modulate nuclear processes such as gene transcription DNA replication, DNA repair, RNA processing, and mRNA transport. However, the interplay between nuclear architecture and gene expression is poorly understood. We propose to elucidate the impact of silencing the prominent transcription factor, TCF7L2, the major effector of the WNT signaling pathway, on the transcriptional equilibrium and nuclear architecture of the nucleus in human colorectal cancer cells. Our multidisciplinary approach combines targeted silencing of TCF7L2, 3D-FISH, RNA-seq, and Hi-C chromosome conformation capture, in parallel with mathematical modeling to delineate structure/function relationships in the interphase nucleus. This approach will elucidate the intricacies of a dynamic cellular signaling pathway in three-dimensional space.
Citation Format: Markus A. Brown. Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and nuclear structure [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 5492. doi:10.1158/1538-7445.AM2017-5492
Abstract 5498: Autoregulation of protein kinase D1 (PRKD1) expression in prostate cancer
Authors: Nickkholgh Bita , Sivanandane Sittadjody 
Published: July 2017

Abstract
Protein kinase D1 (PRKD1) is down regulated in gastric, breast and prostate cancer. Several regulatory mechanisms modulate PRKD1 activity in cancers. In colon cancer, it has been shown that PRKD1 is down regulated by nuclear beta-catenin. We explored whether beta-catenin is involved in regulation of PRKD1 expression in prostate cancer as well. A CHIP assay performed using prostate cancer LNCaP cell lysate and pull down with beta -catenin antibody, which demonstrated recruitment of beta -catenin to promoter of PRKD1 gene as well as at downstream regions in the gene suggesting that beta -catenin could be involved in PRKD1 regulation. To identify the exact binding site of beta-catenin to PRKD1 gene, we carried out CHIP sequencing. The beta -catenin protein complex was bound to a 166 bp sequence near exon 2 (chr14:29899631-29899796). Because beta -catenin is a coactivator and not a known transcription factor, we performed a transcription factor promoter array, which showed that the MYC/MAX transcription factor complex may be the mediator of the regulatory effect of beta -catenin on PRKD1 expression. We validated the results by performing CHIP assay using MYC and MAX antibodies which showed recruitment of both MYC and MAX to the same beta -catenin binding site to PRKD1. In order to assess the functional impact of beta -catenin regulation of PRKD1 in prostate cancer, beta-catenin mutated at threonine
120 residue (we have previously shown that PRKD1 is the only known kinase to phosphorylate the site) demonstrated increased nuclear translocation of beta-catenin and increase down regulation of PRKD1 and increased androgen receptor (AR) activity (increased AR activity is well established to be associated with PC progression). Our data has identified a novel auto-regulatory mechanism of PRKD1 expression through beta-catenin phosphorylation.
Citation Format: Bita Nickkholgh, Sittadjody Sivanandane. Autoregulation of protein kinase D1 (PRKD1) expression in prostate cancer [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 5498. doi:10.1158/1538-7445.AM2017-5498
Abstract 5500: KMT2C directs estrogen receptor activity in normal and transformed mammary cells
Authors: Gala Kinisha , Sinha Amit , Sanchez-Vega Francisco , Chung Young Rock , Hseih James , Berger Michael , Schultz Nikolaus , Pastore Alessandro , Abdel-Wahab Omar , Chandarlapaty Sarat 
Published: July 2017

Abstract
Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that regulates proliferation and differentiation in mammary epithelial cells. ERα activity is likely dependent on the actions of pioneer factors and H3K4 methyltransferases which can establish a genomic landscape permissive for ERα binding. Here, we identify the H3K4 methyltransferase KMT2C as essential for ERα activity in mammary gland development and ER+ breast cancer growth. KMT2C suppression decreases estrogen-dependent gene expression and causes H3K4me1 loss at ERα target gene enhancers. Consequently, KMT2C loss selectively suppresses estrogen-driven breast cancer proliferation. Moreover, mammary-specific Kmt2c knockout mice have defects in pubertal ductal formation similar to Esr1 deficient mice. Although KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. Consistent with this, gene expression signatures of KMT2C loss are associated with poor outcomes. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples mammary phenotypes from hormone availability.
Citation Format: Kinisha Gala, Amit Sinha, Francisco Sanchez-Vega, Young Rock Chung, James Hseih, Michael Berger, Nikolaus Schultz, Alessandro Pastore, Omar Abdel-Wahab, Sarat Chandarlapaty. KMT2C directs estrogen receptor activity in normal and transformed mammary 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 5500. doi:10.1158/1538-7445.AM2017-5500
Abstract 5504: Regulation of the receptor for advanced glycation end products by estrogen receptor ligands in endometrial cancer
Authors: Davies Julia , Gonzalez Deyarina , Conlan R.Steven 
Published: July 2017

Abstract
Endometrial cancer has numerous established risk factors including excessive unopposed estrogen exposure, tamoxifen, obesity and polycystic ovary syndrome (PCOS). These risk factors may promote inflammation, an important hallmark of cancer. Since the endometrium is a site of regular and repeated inflammation during the menstrual cycle, the regulation of inflammation may be involved in endometrial cancer. The receptor for advanced glycation end products (RAGE) stimulates numerous inflammatory signalling pathways and its expression is elevated in a number of inflammatory pathologies including diabetes and more recently cancer. This work aims to investigate the regulation of RAGE by estrogen receptor ligands in endometrial cancer. RAGE and estogen receptor isoform protein expression were examined in a patient cohort by immunohistochemistry. RAGE and ER isoform expression was assessed following estrogen receptor ligand exposure in both type I and type II endometrial cancer cell line models. ERα, ERβ, p65 and ER co-regulator recruitment to the RAGE promoter following ER ligand treatment was determined in vitro by chromatin immunoprecipitation. Data revealed (i) RAGE and ER isoform endometrial expression is altered in endometrial cancer patients and patients receiving tamoxifen compared to postmenopausal women, (ii) RAGE is expressed in type I and II endometrial cancer cell lines and its expression can be modulated by estrogen and tamoxifen exposure, and (iii) by chromatin immunoprecipitation, estrogen receptor ligands were shown to alter ERα, ERβ and ER co-regulator binding at the RAGE promoter. To conclude, results from this work suggest RAGE is associated with endometrial cancer development. Once clinically validated, RAGE and associated targets investigated in this study could be potentially used as a panel of endometrial cancer biomarkers and may also be used to indicate if patients are at risk of the adverse agonist action of tamoxifen in the endometrium.
Citation Format: Julia Davies, Deyarina Gonzalez, R.Steven Conlan. Regulation of the receptor for advanced glycation end products by estrogen receptor ligands in endometrial cancer [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 5504. doi:10.1158/1538-7445.AM2017-5504
Abstract 5541: Identification of sod and sod2 as potential prognostic biomarkers for patients with non-small cell lung cancer
Authors: Yin Chen , Wang Ren , Li Xiao-xing , Yang Yang , Zhang Mei-yin , Wang Hui-Yun , Zheng Steven X. 
Published: July 2017

Abstract
Backgrounds: Reactive oxygen species (ROS) is accumulated in cancer cells related to increased metabolism, which is characteristic of cancer progression. With the rapid advance of cancer research, redox regulation has drawn more and more attentions. The superoxide dismutases SOD1 and SOD2 are essential enzymes for eliminating ROS. To date, SOD1 or SOD2 have not been well characterized in non-small cell lung cancer(NSCLC). Here we compared the expression of SOD proteins between normal and cancer tissues and investigated its prognostic significance in NSCLC patients.
Method: we detected the expression of SOD1 and SOD2 in 178 NSCLC samples by immunohistochemistry and their clinical significances were analyzed. Western blotting is used to confirm the protein level of SOD1 and SOD2 in the normal and cancer tissues of NSCLC patients.
Results: The expression of SOD1 and SOD2 is significantly higher in both
adenocarcinoma or squamous cell carcinoma (p&lt;0.0001), compared to matched adjacent normal tissues. Correlation analysis indicates that SOD1 expression is reversely associated with TNM stage, and SOD2 is negatively correlated with tumor size, tumor number and TNM stage remarkably (all p &lt;0.05). Moreover, higher expression of SOD1 and SOD2 is correlated with better prognosis of NSCLC patients. Finally, Univariate and multivariate Cox regression modes further indicate that SOD1 and SOD2 can be used as independent prognostic factors in NSCLC patients.
Conclusion: Higher expressions of SOD1 and SOD2 in NSCLC tissues are observed compared to adjacent tissues and indicate better prognosis, suggesting that SOD proteins are potentially useful biomarkers for prognostic evaluation of patients with NSCLC.
Key Words: Reactive oxygen species; Non-small cell lung cancer; Superoxide dismutase 1/2; Prognosis.
Citation Format: Chen Yin, Ren Wang, Xiao-xing Li, Yang Yang, Mei-yin Zhang, Hui-Yun Wang, Steven X. Zheng. Identification of sod and sod2 as potential prognostic biomarkers for patients with non-small cell lung cancer [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 5541. doi:10.1158/1538-7445.AM2017-5541
Abstract 5560: Systemic map of protein phosphatase 2A (PP2A)-regulated phosphotargets and drug responses in cancer cells
Authors: Kauko Otto , Imanishi Susumu , Kulesskiy Evgeny , Laajala Teemu D. , Yetukuri Laxmana , Padzik Artur , Jumppanen Mikael , Haapaniemi Pekka , Yadaw Bhagwan , Suni Veronika , Varila Taru , Corthals Garry , Krister Wennerberg , Aittokallio Tero , Westermarck Jukka 
Published: July 2017

Abstract
Despite the pivotal role of phosphatases in cancer cell signalling, systemic understanding of phosphatase targets is still at infancy. Protein phosphatase 2A (PP2A) is a human tumor suppressor complex. PP2A inhibition is a requirement for human cell transformation and PP2A regulates many cancer critical signalling pathways. Importantly, emerging data indicates that reactivation of PP2A tumor suppressor activity could provide entirely novel approach for cancer therapy. Here, we present first systemic analysis of phosphoprotein targets (dephosphorylome) regulated by PP2A in cancer cells. Based on data, PP2A regulates cancer critical signalling pathways, including entire EGFR-RAS-RAF-MEK-ERK cascade, and functions as a master regulator of MYC function. At network level, PP2A targets critical cellular processes such as chromosome organization, RNA splicing, and nuclear envelope assembly. Surprisingly, soft clustering of PP2A dephosphorylome revealed that most phospho-target residues are subject to only unidirectional regulation in cancer cells. Moreover, targets show intracellular gradient where phosphatase inhibition dominates nuclear phosphorylation balance. Since phosphoregulation is critical for cancer drug responses, dephosphorylome was correlated with cancer cell responses to over 300 drugs. Importantly, cancer therapies could be broadly classified based on their dephosphorylome, both at quantitative and qualitative manner. Finally, we demonstrate the utility of this large dataset by validating the role of PP2A in MEK inhibitor resistance in KRAS mutant cancer cells via regulation of RAF, mTor and MYC. The study presents first systemic resource to understand potential of PP2A manipulation in cancer cell signalling and drug responses. The study also uncovers generally important insights to phosphoregulation.
Citation Format: Otto Kauko, Susumu Imanishi, Evgeny Kulesskiy, Teemu D. Laajala, Laxmana Yetukuri, Artur Padzik, Mikael Jumppanen, Pekka Haapaniemi, Bhagwan Yadaw, Veronika Suni, Taru Varila, Garry Corthals, Wennerberg Krister, Tero Aittokallio, Jukka Westermarck. Systemic map of protein phosphatase 2A (PP2A)-regulated phosphotargets and drug responses in 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 5560. doi:10.1158/1538-7445.AM2017-5560
Abstract 5573: A high-affinity Optide (optimized peptide) inhibitor of the Hippo pathway’s YAP-TEAD interaction
Authors: Crook Zachary R. , Bradley Philip , Sevilla Gregory , Friend Della , King Chris , Mhyre Andrew , Strong Roland , Baker David , Olson James M. 
Published: July 2017

Abstract
The HIPPO pathway plays a critical role in contact inhibition, a pathway that is commonly dysregulated in many human cancers (including liver, colon, ovarian, and lung). The signaling pathway culminates in the intranuclear interaction of the transcriptional co-activator YAP and the transcription factor TEAD. This is representative of a number of cancer driving pathways that have proven nearly impossible to drug, as they are mediated by intracellular protein-protein interactions. High throughput screening campaigns with small molecule libraries have failed to provide specific, high affinity binders capable of disrupting larger protein-protein interfaces (such as YAP-TEAD), while at the same time, antibodies cannot penetrate the cell membrane to access cytosolic and nuclear targets. Optides are small disulfide-knotted peptides (knottins) that are large enough to interfere with protein-protein interactions, but small enough to access compartments beyond the reach of antibodies. Examples include the calcines, activators of sarcoplasmic reticulum ryanodine receptors, and BLZ-100, a knottin-fluorophore conjugate that is capable of accumulating in a wide range of tumor types. Using the computational design software Rosetta, we created a library of Optides designed to interact with TEAD in locations that overlap YAP binding. Mammalian surface display screening against soluble TEAD yielded a candidate (Hit1) that binds TEAD with nanomolar affinity and inhibits YAP binding. Affinity maturation, using site saturation mutagenesis, produced an improved sub-nanomolar variant (IV1) with potent YAP inhibition. This variant was also found to be highly resistant to reduction and proteolysis, crucial for a disulfide-knotted peptide with a cytosolic target in the proteinase-rich tumor milieu. With this highly potent YAP inhibitor, efforts are now focused on cell penetration and biodistribution with the long-term goal of advancing a clinical development candidate.
Citation Format: Zachary R. Crook, Philip Bradley, Gregory Sevilla, Della Friend, Chris King, Andrew Mhyre, Roland Strong, David Baker, James M. Olson. A high-affinity Optide (optimized peptide) inhibitor of the Hippo pathway’s YAP-TEAD interaction [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 5573. doi:10.1158/1538-7445.AM2017-5573
Abstract 5576: BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model
Authors: Kazerounian Shiva , Sarma Aishwarya , Gaur Nidhi , Nastke Maria D. , Dadali Tulin , Diers Anne R. , Gesta Stephane , Vishnudas Vivek K. , Sarangarajan Rangaprasad , Narain Niven R. 
Published: July 2017

Abstract
BPM 31510, a clinical stage nanodispersion of ubidecarenone, demonstrates anti-tumor effects by eliciting an anti-Warburg metabolic switch in cancer. Previous studies in an immune compromised PaCa2 xenograft model has unequivocally demonstrated significant efficacy of BPM 31510 on tumor volume and survival. The fundamental property of BPM 31510 to influence mitochondrial bioenergetics and the recognized interplay between T cell metabolism and maturation prompted investigation into the effects of BPM 31510 on T lymphocyte functions in eliciting anti-cancer effects. In this study BPM 31510 selectively influenced activation and maturation of T cells in murine peripheral blood mononuclear cells (PBMCs). Moreover, in addition to determining changes in the CD3+ population, changes in surface expression of PD-1 and CTLA4 along with the IFN-γ secretion were examined. Murine cancer cell lines exposed to BPM 31510 were associated with variable sensitivity with highly metabolic tumor types being most sensitive. Next, the anti-cancer activity of BPM 31510 in an in vivo immunocompetent syngeneic Pan02 rodent model was investigated. Murine Pan02 pancreatic cancer cells were implanted subcutaneously into C57BL/6 mice. Tumors with mean volume of 80 mm3 were treated twice a day with vehicle control or BPM 31510 at 25, 50, 100 mg/kg, administered intraperitoneal. Tumor volumes were measured every 4 days. At day 21 post treatment, tumors were harvested and analyzed for the level of infiltrating immune cells by immunofluorescent staining with CD8+ for T cells and F4/80 for tumor macrophages. These results demonstrate a dose-dependent reduction in tumor volume following 21 days of BPM 31510 treatment. In summary, BPM 31510 exerts potent anti-tumor effects through its dual function of modulating tumor cell metabolism and potentially influencing immune check-point to improve overall survival outcomes.
Citation Format: Shiva Kazerounian, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Tulin Dadali, Anne R. Diers, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model [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 5576. doi:10.1158/1538-7445.AM2017-5576