bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 879: Single cell analysis resolves combinatory targeted therapy for arresting the BRAFi-induced cellular dedifferentiation of metastatic melanomas
Authors: Su Yapeng , Wei Wei , Xue Min , Robert Lidia , Tsoi Jennifer , Graeber Thomas , Ribas Antoni , Heath James 
Published: July 2016

Abstract
Targeted therapy that inhibits the BRAF (V600E) protein has shown impressive initial responses in metastatic melanoma patients. However, acquired drug resistance, derived from tumor heterogeneity, always limits its efficacy and compromises its treatment outcomes. Melanocyte to neural crest transition (MNT) has been observed to play crucial role in early stage adaptive drug tolerance, and the mathematic modeling indicates the transition is contributed from both stochastic phenotypic transition and non-genetic selection. Whole transcriptomic analysis enriched important signaling proteins that are involved in the resistance development process. Single cell proteomic analysis of those proteins was performed on patient-derived melanoma models to further study the early stage drug tolerance. This resolves how protein signaling network coordination rewires in the process, which cannot be resolved from proteomic analysis of bulk tumor tissue. Signaling network coordination analysis indicates that co-inhibiting the hubs of the network (MEK, NFKB-p65) could keep cells in the drug-susceptible stages. The combination therapy that co-inhibits mutant BRAF, MEK and NFKB-p65 together successfully arrested the MNT transition and induced a sustained tumor growth suppression in multiple patient-derived melanoma cell lines. This study provides us a brand-new way of using single cell proteomic analysis to infer effective combinations by resolving protein signaling network coordination that is inaccessible through traditional bulk-level proteomic measurement.
Citation Format: Yapeng Su, Wei Wei, Min Xue, Lidia Robert, Jennifer Tsoi, Thomas Graeber, Antoni Ribas, James Heath. Single cell analysis resolves combinatory targeted therapy for arresting the BRAFi-induced cellular dedifferentiation of metastatic melanomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 879.
Abstract 886: Notch signaling activates B-cell specific enhancers to drive oncogene targets in B-cell lymphoma
Authors: Ryan Russell J. , Petrovic Jelena , Rausch Dylan M. , Lee Winston , Kluk Michael , Donohue Laura , Gillespie Shawn , Aster Jon C. , Pear Warren S. , Bernstein Bradley E. 
Published: July 2016

Abstract
Recurrent gain-of-function mutations in genes encoding Notch receptors are associated with poor clinical outcome in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but genome-wide functional targets of Notch signaling in B cells have not been characterized.
We identified genome-wide binding sites for Notch transcription factor (TF) complexes, using antibodies specific for intracellular NOTCH1 and its binding partner RBPJ, in CLL and MCL lymph node biopsies, and lymphoma cell lines. We employed a gamma-secretase inhibitor washout strategy to rapidly modulate mutant NOTCH1 protein activation in complementary lymphoma cell line models of ligand-dependent and ligand-independent Notch signaling, and performed RNA-sequencing and genome-wide enhancer acetylation profiling in both the “notch on” and “notch off” states. These data identify a common set of functional Notch target genes in B-cell lymphoma that includes both canonical Notch targets as well as B-cell-specific target genes. The latter are frequently associated with adjacent B-cell-specific enhancers that show direct Notch TF binding and Notch-signaling-dependent histone acetylation. Notch-activated target genes include MYC and other TFs implicated in B-cell lymphoma, and are significantly enriched for mediators of targetable oncogenic lymphoma signaling pathways, (B-cell receptor, toll-like receptor, JAK-STAT, MAP kinase, and G-protein signaling pathways, all FDR q-value &lt; 1e-3 in KEGG and / or Reactome analyses). Many B-cell Notch target genes show significantly increased expression in lymph nodes from patients with NOTCH1 mutant vs. wild-type CLL. Notch target genes are also up-regulated in lymph node- versus peripheral blood-derived CLL cells, consistent with immunohistochemical evidence for microenvironment-dependent Notch signaling activation in the CLL lymph node. Combined small-molecule inhibition of Notch and B-cell receptor signaling showed a synergistic anti-proliferative effect in Notch-dependent lymphoma cells.
Our data reveal the functional regulome of Notch signaling in small B-cell lymphoma, and may have implications for the role of Notch signaling in normal B-cell development. These findings suggest novel strategies for rational combination therapy in CLL and MCL.
Citation Format: Russell J. Ryan, Jelena Petrovic, Dylan M. Rausch, Winston Lee, Michael Kluk, Laura Donohue, Shawn Gillespie, Jon C. Aster, Warren S. Pear, Bradley E. Bernstein. Notch signaling activates B-cell specific enhancers to drive oncogene targets in B-cell lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 886.
Abstract 891: Dual defects of MDM2/MDMX-p53 pathways cause global metabolic disruption and enhance tumorigenesis
Authors: Lu Hua , zhang Yi-wei , Liao Peng , Liao Wenjuan , Chen Jiaxiang , Zeng Shelya X. 
Published: July 2016

Abstract
Although recent discoveries have linked the tumor suppressing functions of p53 to its regulation on cellular metabolism, the exact signaling pathways underlying how p53 is activated in response to various metabolism stresses, and how p53 coordinates the systemic metabolism homeostasis and further blocks tumorigenesis remain largely unclear. Previous studies have shown that the mice containing a single knock-in at cysteine residue 305 of MDM2 (MDM2C305F) is defective in ribosomal stress (RS) induced p53 activation and display severe nutrient shortage-induced hepatosteatosis. And very recently we found that in response to metabolic stress (MeS), AMPK directly phosphorylates serine 342 of MDMX, leading to p53 activation, which is defective in MDMX3SA mice harboring a mutant MDMX with S341A, S367A and S402A mutations. In the current study, we want to determine if the dual defects in the MDM2/MDMX-p53 pathways might thoroughly impair p53's ability to regulate metabolic homeostasis and thus favor metabolism-related tumorigenesis, by generating a double knock-in (DKI) MDMX3SA/MDM2C305F mouse line. Our results indicate that DKI mice on normal chow diet exhibit mild, but significant, metabolism abnormalities, including increased body weight, higher fasting-glucose level and impaired glucose tolerance, which is exacerbated by high-fat-diet feeding. Consistently, MEFs isolated from DKI mice possess higher capacity of differentiation into adipocytes, and less beige fat is induced in the subcutaneous white adipose tissue of DKI mice after chronic cold exposure. Furthermore, we observe that the survival rate of DKI mice is significantly lower compared to either control or single knock-in groups, which may be due to the higher morbidity of cancers in DKI mice, including hepatoma, lymphoma and lung carcinoma. Because of these observations, we further specifically investigate if dual defects of these p53 activation pathways will accelerate hepatocellular carcinogenesis or not. We indeed find that treatment of carcinogen DEN causes more and bigger tumor nodules in the liver of DKI mice. These results suggest that both RS-MDM2-p53 and MeS-MDMX-p53 pathways play important roles in regulation of global metabolism, and dual defects of these pathways benefit metabolism-related tumor formation and growth. Further study is required to establish the direct effect of the p53 pathway defects-mediated metabolic disruption on tumorigenesis, and determine the underlying mechanisms.
Citation Format: Hua Lu, Yi-wei zhang, Peng Liao, Wenjuan Liao, Jiaxiang Chen, Shelya X. Zeng. Dual defects of MDM2/MDMX-p53 pathways cause global metabolic disruption and enhance tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 891.
Abstract 899: Cancer protection associated with dietary methyl donor deficiency is characterized by persistent changes to epithelial proliferation and metabolism
Authors: Hanley Matthew P. , Rosenberg Daniel W. 
Published: July 2016

Abstract
The role of folate one-carbon metabolism in colorectal cancer development is incompletely understood, and nutritional intervention studies have produced conflicting results. We previously demonstrated that a diet deficient in the methyl donors folic acid, methionine, choline and vitamin B12, and supplemented with homocysteine, reduces intestinal tumor incidence by greater than 95% in ApcMin/+ mice. Here we extend these findings to a second mouse tumor model, ApcÄ14, and further show that the cancer protection afforded by even short-term dietary methyl donor deficiency (MDD) is long-lasting. Eleven weeks of MDD followed by methyl donor repletion was sufficient to maintain tumor suppression for at least 7 additional weeks (22.2 ± 3.5 vs 70.2 ± 4.6 intestinal tumors; p &lt; 0.001). Sustained tumor protection was associated with altered intestinal crypt homeostasis. MDD increased the proportion of intestinal epithelial cells undergoing apoptosis in normal crypts and in tumors (4.9- and 3.2-fold, respectively), while reducing cell proliferation (Ki-67) and mitosis (PHH3). In addition, metabolomic profiling and metabolite set enrichment analysis (MSEA) revealed that tumor protection is associated with persistent alterations to metabolic pathways related to cellular proliferation, including glutamine metabolism, biogenic amine synthesis, nucleotide salvage and glutathione synthesis. Taken together, these results indicate that even a temporary dietary methyl donor restriction in cancer-prone mice can induce persistent changes to the intestinal epithelium that provide long-lasting protection in adult mice.
Citation Format: Matthew P. Hanley, Daniel W. Rosenberg. Cancer protection associated with dietary methyl donor deficiency is characterized by persistent changes to epithelial proliferation and metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 899.
Abstract 903: IFN-ã induced PD-L1 on tumor and host cells co-operatively prevents tumor immune elimination after cancer immunoediting
Authors: Noguchi Takuro , Ward Jeffrey P. , Gubin Matthew M. , Arthur Cora , Schreiber Robert D. 
Published: July 2016

Abstract
Tumor cells can escape immune destruction via engaging the PD-1/PD-L1 inhibitory pathway. However since PD-L1 is induced on many different cell types by IFN-ã, the importance of PD-L1 on tumor versus host cells in mediating immune escape remains unclear. In this study, we assessed the role of PD-L1 expression on two closely-related but distinct clones derived from the same d42m1 methylcholanthrene (MCA)-induced sarcoma line. Edited d42m1-T3 sarcoma cells grow progressively in wild type (WT) mice but are rejected in mice treated with anti-PD-L1. Upregulation of PD-L1 was observed on both immune and tumor cells in vivo. To assess the role of PD-L1 specifically on tumor cells, we generated d42m1-T3 cells lacking PD-L1 (T3ÄPDL1) using CRISPR-Cas9. T3ÄPDL1 cells were spontaneously rejected in naïve syngeneic WT mice but formed progressively growing tumors in Rag2-/- mice. To explore the role of host-cell expressed PD-L1, we challenged WT mice with 3-fold higher numbers of T3ÄPDL1 cells and found that the tumor cells formed progressively growing tumors in WT mice. However, when tumor bearing mice injected with the high dose of T3ÄPDL1 cells were treated with blocking PD-L1 mAb, they all rejected their tumors. Thus, PD-L1 expression on both tumor and host cells plays a critical role in preventing immune elimination of edited MCA sarcoma cells. Alternatively highly immunogenic, unedited d42m1-T9 sarcoma cells were spontaneously rejected in WT mice due to the presence of the strong rejection antigen, mutant Spectrin-â2. Enforced expression of PD-L1 on unedited d42m1-T9 cells to levels similar to those induced under physiologic in vivo conditions did not alter the regressor phenotype of these cells. In contrast, enforced overexpression of PD-L1 on d42m-T9 cells to levels that were 20 fold higher than physiologic led to formation of progressively growing tumors in WT mice. Thus, physiologic levels of PD-L1 expression on highly immunogenic unedited tumor cells are not sufficient to counteract immune effector mechanisms driven by “strong” tumor antigens. This result shows that adaptive immune resistance occurs only on tumor cells that have undergone immunoediting.
Citation Format: Takuro Noguchi, Jeffrey P. Ward, Matthew M. Gubin, Cora Arthur, Robert D. Schreiber. IFN-ã induced PD-L1 on tumor and host cells co-operatively prevents tumor immune elimination after cancer immunoediting. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 903.
Abstract 926: Pentraxin 3 is responsive to the activation of CCAAT/enhancer binding delta and promotes cancer progression in the tumor microenvironment
Authors: Chi Jhih-Ying , Wang Ju-Ming 
Published: July 2016

Abstract
This lack of understanding especially impacts the design of anticancer treatments. It is a common observation in the clinic that recurrent cancers, and particularly anticancer drug-resistant cancers, are more difficult to treat because they spread faster than the original tumor. CCAAT/enhancer binding protein delta (CEBPD) was activated in M2 macrophages and myofibroblasts/cancer-associated fibroblasts (CAFs) and contributed to metastasis, invasion and recurrence of cancer cells in response to PGE2 and the anticancer drugs. We further found that pentraxin 3 (PTX3) was activated in response to CEBPD induction and involved in migration and invasion of breast cancer cells, and the same phenomenon was also observed in drug-resistant cancers. Interestingly, we found that a recombinant PTX3 protein containing the C-terminal region (pPTX3) showed an opposite tumorigenic effect to the mammalian PTX3. The results suggest that PTX3 could be a promising target for preventing the metastasis/invasion of cancers and treating drug-resistant cancers.
Citation Format: Jhih-Ying Chi, Ju-Ming Wang. Pentraxin 3 is responsive to the activation of CCAAT/enhancer binding delta and promotes cancer progression in the tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 926.
Abstract 938: Activation of ATR/CHK1 checkpoint is critical for mediating p53-dependent autophagy and pro-inflammatory VEGF production in human bronchial epithelial cells under fine particulate matters (PM2.5) exposure
Authors: Song Lun 
Published: July 2016

Abstract
The epidemiological and clinical studies have increasingly shown that fine particulate matters (PM2.5) exposure is associated with exacerbation of airway inflammation, which might results in the occurrence of lung cancer. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is a crucial issue for the study of PM2.5 toxicity. In the current study, we found that exposure of human bronchial epithelial cells (Beas-2B) to the winter PM2.5 collected in Wuhan, the south city of China, induced an significant up-regulation of VEGF production, a typical signaling event functionally in controlling chronic airway inflammation and vascular remodeling. Further investigations showed that autophagy was induced upon PM2.5 exposure and then mediated VEGF up-regulation by activating Src/STAT3 pathway in the Beas-2B cells. When exploring the upstream signaling events responsible for autophagy induction, we disclosed the requirement of p53 activation and its downstream target DRAM expression for the induction of autophagy, which results thus have extended the role of p53/DRAM-dependent autophagy beyond cell fate determination under genotoxic stresses and to the control of pro-inflammatory cytokine production. Moreover, PM2.5 exposure strongly induced activation of ATR/CHK1 axis, which subsequently triggered p53-dependent autophagy and VEGF production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genome integrity and the airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.
Citation Format: Lun Song. Activation of ATR/CHK1 checkpoint is critical for mediating p53-dependent autophagy and pro-inflammatory VEGF production in human bronchial epithelial cells under fine particulate matters (PM2.5) exposure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 938.
Abstract 944: The effects of GnRH-(1-5) on endometrial cancer cell lines
Authors: Larco Darwin O. , Cho-Clark Madelaine J. , Sorini Maya , Lee Cameron , Wu. T. John 
Published: July 2016

Abstract
The Gonadotropin-Releasing Hormone (GnRH) is a central regulator of reproductive function and behavior. In the periphery, GnRH is secreted by gynecologic tissues to exert local effects. Furthermore, GnRH is processed in the extracellular environment by the metalloendopeptidase EP24.15 to generate the bioactive metabolite, GnRH-(1-5). We have previously demonstrated that GnRH-(1-5) transactivates the epidermal growth factor receptor (EGFR) pathway to promote cell migration by binding the orphan receptor GPR101 in the Ishikawa and ECC-1 endometrial cancer cell lines. In this study, we sought to determine whether the effects of GnRH-(1-5) were dependent on the stage of the endometrial cancer. Cell lines ACI-181, ACI-52, and ACI-80 derived from endometrial cancers representative of stages 1, 2, and 3 respectively were tested in their response to GnRH-(1-5) treatment. Furthermore, the expression of GPR101 was confirmed by western blot analysis. Treatment with 100nM GnRH-(1-5) did not have significant changes in phospho-EGFR (pEGFR) levels in all ACI cell lines. However, subsequent measurement of ERK phosphorylation demonstrated that ACI-181 cells treated with GnRH-(1-5) had significantly (p &lt; 0.05) increased levels in the pERK2 subunit but not pERK1, which parallels our initial findings in the Ishikawa cell line. No changes in pERK1/2 levels were determined in the other cell lines. To measure the effect of GnRH-(1-5) on cell migration, we implemented a wound closure assay. Interestingly, ACI-181 and ACI-52 cells had increased migration in response to GnRH-(1-5) treatment. To determine whether another pro-migratory pathway is regulated by GnRH-(1-5) in these cells, we measured TGF-β bioactivity using a cell-based assay from conditioned media of cells treated with GnRH-(1-5). We found that ACI-181 and ACI-52 cells had significantly (p&lt;0.05) increased TGF-β bioactivity in response to GnRH-(1-5), indicating that these cells produced higher levels of bioactive TGF-β. It is likely that TGF-β and/or other growth factors may promote pro-survival and/or pro-migratory signaling cascades via an autocrine mechanism. These results further suggest that GnRH-(1-5) may exert differential effects on endometrial cancer cells that are not dependent on cancer progression.
Funding Sources: This research was supported by grants from the John P. Murtha Cancer Center at Walter Reed National Military Medical Center through the Uniformed Services University and the National Science Foundation (IOS-1052288).
Citation Format: Darwin O. Larco, Madelaine J. Cho-Clark, Maya Sorini, Cameron Lee, T. John Wu. The effects of GnRH-(1-5) on endometrial cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 944.
Abstract 956: Anticancer effects of silibinin-induced small nucleolar RNA 11B on bladder cancer cells
Authors: Yamamura Soichiro , Mitsui Yozo , Majid Shahana , Nip Hannah , Bucay Nathan , Saini Sharanjot , Deng Guoren , Shahryary Varahram , Dahiya Rajvir , Tanaka Yuichiro 
Published: July 2016

Abstract
Silibinin is the major active constituent of silymarin, an extract of milk thistle seeds. Silibinin has been shown to have significant anti-cancer effects in a variety of malignancies. However, the molecular mechanisms of silibinin action in bladder cancer have not been reported. In the present study, we found that silibinin (10 μM) significantly suppressed proliferation and invasion of T24 and UM-UC-3 bladder cancer cells. We analyzed various pathways as possible mechanisms of silibinin action using RNA-Seq technology in bladder cancer cell lines. Analysis of RNA-seq data identified silibinin targets that down-regulate the actin cytoskeleton pathway. Analysis of RNA-seq data also identified the mitogen-activated protein (MAP) kinase signaling pathway as a silibinin-down-regulated pathway. These pathways were also found to crosstalk through Ras and phosphatidylinositide 3-kinase (PI3K). These data show that silibinin anti-cancer effects are through down-regulation of actin cytoskeleton and MAP kinase pathways in bladder cancer. We also found that silibinin induced small nucleolar RNA 11B (SNORD11B) and that SNORD11B suppressed proliferation and invasion of bladder cancer cells. We will discuss the pathway of the anti-cancer effects of SNORD11B.
Citation Format: Soichiro Yamamura, Yozo Mitsui, Shahana Majid, Hannah Nip, Nathan Bucay, Sharanjot Saini, Guoren Deng, Varahram Shahryary, Rajvir Dahiya, Yuichiro Tanaka. Anticancer effects of silibinin-induced small nucleolar RNA 11B on bladder cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 956.