bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3501: Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling
Authors: Carbone Carmine , Piro Geny , Santoro Raffaela , Simionato Francesca , Merz Valeria , Zecchetto Camilla , Scarpa Aldo , Tortora Giampaolo , Melisi Davide 
Published: August 2018

Abstract
Background: Solid epidemiological evidences connect obesity with incidence, stage, and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions.
Methods: We studied the role of factors secreted by two adipogenic model systems from primary human Bone Marrow Stromal Cells (hBMSC) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS).
Results: We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member Receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells.
Conclusions: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to
select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.
Citation Format: Carmine Carbone, Geny Piro, Raffaela Santoro, Francesca Simionato, Valeria Merz, Camilla Zecchetto, Aldo Scarpa, Giampaolo Tortora, Davide Melisi. Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling [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 3501.
Abstract 3502: Chemoproteomics provide insights into cell surface reprogramming during KRAS-mediated transformation
Authors: Nandagopal Neethi , Aubert Léo , Nourreddine Sami , Lavoie Geneviève , Roux Philippe 
Published: August 2018

Abstract
KRAS is among the most frequently mutated genes driving human cancers, including ~45% of colorectal cancers (CRC). Despite decades of research, mutant KRAS is considered undruggable, and is frequently associated with resistance to chemotherapy and other targeted therapies. While the effect of mutant KRAS on regulating intracellular signaling events is well studied, much less is known about its impact on the cell surface proteome (surfaceome), which constitutes the predominant therapeutic target for FDA-approved drugs. To study the cell surfaceome, we optimized a chemoproteomics approach that selectively isolates cell surface proteins and allows their relative quantification using mass spectrometry. When comparing normal intestinal cells to their counterparts expressing oncogenic KRAS (G12V), we identified 104 (~13%) and 170 (~22%) cell surface proteins that were significantly upregulated or downregulated, respectively, in KRAS-transformed cells. Overall, a myriad of proteins, including receptors, solute carriers, adhesion molecules, etc., were modulated by mutant KRAS, and their potential roles in KRAS-mediated transformation are currently being studied. We also found that most of the cell surface proteins were altered in response to transcriptional changes induced by KRAS signaling, and due to increased global endocytosis in KRAS-mutated cells. Our study suggests potential cell surface proteins that could be targeted in KRAS-mutant cells, which will be verified in subsequent studies using human CRC models. Our work helps assemble a global view of how oncogenic KRAS alters the spatial distribution of several cell surface proteins, and thereby potentially impacts tumor functions and therapeutic response.
Citation Format: Neethi Nandagopal, Léo Aubert, Sami Nourreddine, Geneviève Lavoie, Philippe Roux. Chemoproteomics provide insights into cell surface reprogramming during KRAS-mediated transformation [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 3502.
Abstract 351: Epigenetic mechanisms regulate DNA amplification and drug-resistant gene selection
Authors: Mishra Sweta , Rechem Capucine Van , Chakraborty Damayanti , Whetstine Johnathan R. 
Published: August 2018

Abstract
DNA copy gains and amplifications are often associated with tumorigenesis, poor prognosis and drug resistance. Little is known about how these regions of the genome are selected for amplification. Our group discovered that modulation of epigenetic factors and their associated chromatin states control DNA copy gains of drug-resistant regions. In fact, transient site-specific copy number gains (TSSGs) occur in both normal and cancer cells upon manipulation of a histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A. However, the mechanism by which KDM4A is targeted to specific genomic regions and whether additional chromatin regulators are involved in this process were unknown. To begin addressing these questions, we performed a series of unbiased genetic screens against all the histone lysine-modifying enzymes and followed their ability to generate copy gains of regions within chromosome 1. Our screen uncovered insights into both KDM4A targeting and the identification of other epigenetic factors modulating DNA amplification of drug-resistant regions of the genome. We have uncovered KDM4A-independent DNA amplifications, which established that additional regions are undergoing epigenetic control for amplification. These currently unpublished data will be discussed at the meeting.
Citation Format: Sweta Mishra, Capucine Van Rechem, Damayanti Chakraborty, Johnathan R. Whetstine. Epigenetic mechanisms regulate DNA amplification and drug-resistant gene selection [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 351.
Abstract 3516: Discovery of novel SHMT small molecule inhibitors for cancer treatment
Authors: Bartosik Anna , Guzik Pawel , Sowinska Marta , Gluza Karolina , Krol Marcin , Wrobel Anna , Dreas Agnieszka , Iwanska Faustyna , Zastawna Magdalena , Kulesza Urszula , Boutard Nicolas , Schultz David , Wujkowska Justyna , Pyziak Karolina , Sroka-Porada Agnieszka , Przybylowicz Agnieszka , Adamus Agnieszka , Sieprawska-Lupa Magdalena , Golik Przemyslaw , Kowalczyk Piotr , Brzozka Krzysztof , Rzymski Tomasz , Nowak Mateusz 
Published: August 2018

Abstract
Over-activation of the serine synthesis pathway, upregulation of SHMT2 has been described in over 20% of solid tumors (e.g. breast, lung, colorectal cancers). Such cancer cells are highly dependent on serine. Serine hydroxymethyltransferase (SHMT) plays a key role in a so-called one-carbon pathway, a group of biochemical reactions involved in amino acid metabolism. SHMT catalyzes the conversion of serine to glycine and also plays a role in the folate (vitamin B9) cycle. Antagonists of folate metabolism or antifolates are an established chemotherapy in certain cancers. Folate antagonism disrupts cell division, DNA/RNA synthesis and protein synthesis. Pemetrexed (for non-small cell lung carcinoma, mesothelioma) and methotreaxate (for autoimmune conditions like rheumatoid arthritis and certain cancers) are two well established and effective antifolates. The main drawback with antifolates in cancer treatment, however, is the development of resistance. In this study we report development of a series of small molecule SHMT1/2 inhibitors. Synthetized compounds exert potency in SHMT1/2 biochemical assay as well as in cellular assay (measured by the C13 serine to glycine conversion) with the low nanomolar range. Therapeutic effect of the compounds was investigated in the panel of cancer cell lines with different genetic background as well as with different SHMT2 levels. We identified several cell lines in which tested compounds inhibited cancer cell grow with nM GI50 values. Taken together, presented data supports our rationale for using SHMT1/2 inhibitors as a novel and interesting approach for the cancer therapy.
Citation Format: Anna Bartosik, Pawel Guzik, Marta Sowinska, Karolina Gluza, Marcin Krol, Anna Wrobel, Agnieszka Dreas, Faustyna Iwanska, Magdalena Zastawna, Urszula Kulesza, Nicolas Boutard, David Schultz, Justyna Wujkowska, Karolina Pyziak, Agnieszka Sroka-Porada, Agnieszka Przybylowicz, Agnieszka Adamus, Magdalena Sieprawska-Lupa, Przemyslaw Golik, Piotr Kowalczyk, Krzysztof Brzozka, Tomasz Rzymski, Mateusz Nowak. Discovery of novel SHMT small molecule inhibitors for cancer treatment [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 3516.
Abstract 352: DNA replication licensing factor MCM5 is a target for SETD8 mediated methylation
Authors: Pittella Fabio , Blum Gil , Zhu Yongxia , Senevirathne Chamara , Luo Minkui 
Published: August 2018

Abstract
SETD8 methyltransferase activity is implicated in several fundamental cellular processes such as transcriptional regulation and heterochromatin formation as well as processes that ensures genomic stability including DNA replication and the DNA damage response. It has been proposed that SETD8 affects DNA replication as a positive regulator of origin licensing through H4K20 methylation and by supporting Okazaki fragment processing through PCNA methylation. However, there is no evidence whether other key element in the replication machinery is directly modified by SETD8. To address this question, we used a combination of SILAC-based BPPM (Bioorthogonal Profiling of Protein Methylation) to profile new substrates for SETD8. We genetically engineered SETD8 and identified mutants amenable to accommodate non-native SAM analogues containing a terminal alkyne moiety for click chemistry. The engineered SETD8 can transfer this unique chemical moiety into target proteins for subsequent identification of the modified substrates. Stable cell lines expressing catalytically active or catalytically dead SETD8 mutants were systematically cultured with distinct stable isotope labeled amino acids allowing quantitative proteomic analysis of the identified substrates. With this method we could validate previously known substrates of SETD8 and identify novel targets, including MCM5, a subunit of the hexameric minichromosome maintenance (MCM) DNA helicase complex. MCM5 directly interacts with MCM2 and 3 to form the MCM2-7 hexamer which associates with the origins of DNA replication to form part of the pre-replicative complex (preRC), playing a major role during replication initiation and elongation. We found that SETD8 mediated methylation of MCM5 directly affects its binding affinity to MCM2 and 3. Amino acid substitutions at the methylated lysine further evidenced a stronger binding to its interacting partners contributing to the formation of the MCM hexamer. In addition, CRISPR based modifications on MCM5 methylated lysine affected the replication process resulting in defective cell cycle progression. Taken together our results indicate that MCM5 methylation contributes to the assembly of the MCM complex revealing a novel role for SETD8 in replication initiation. Our findings brings new perspectives on the biological importance of SETD8 during DNA replication.
Citation Format: Fabio Pittella, Gil Blum, Yongxia Zhu, Chamara Senevirathne, Minkui Luo. DNA replication licensing factor MCM5 is a target for SETD8 mediated methylation [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 352.
Abstract 353: Using cancer-associated variants to dissect functions of SETD8
Authors: Zhu Yongxia , Wang Lihui , Senevirathne Chamara , Chen Shi , Silva Fabio Pittella , Luo Minkui 
Published: August 2018

Abstract
Protein lysine methyltransferases (PKMTs) play important roles in carcinogenesis through methylation of histone and non-histone substrates. SETD8 is the sole human methyltransferase for the monomethylation of histone H4 Lys20 (H4K20me1). Besides histone substrates, SETD8 modifies multiple non-histone substrates including proliferating cell nuclear antigen (PCNA), Numb, and p53. The biological functions related to the methyltransferase activity of SETD8 have been implicated in many essential biological processes including DNA replication, DNA damage response, cell cycle regulation, and transcription modulation. The SET domain of SETD8 is required to catalyze the methylation in substrates using the cofactor S-adenosyl-L-methionine (SAM). The C-terminal region post the SET domain (cSET) contains both the cofactor and protein substrate-binding sites. Recent genomics data from samples of cancer patients have revealed distinct variants in the SET domain of SETD8. Missense mutations, such as, E289Q, R292L, V315I, and H347Q were found in multiple types of cancers. To help dissect the roles of SETD8, we proposed the identification and characterization of SETD8 variants with partial loss-of-function phenotypes. Our data showed that overexpression of the SETD8 mutants increased the migration and tumor sphere formation of breast cancer cells without affecting H4K20me1. In vitro biochemical assay also confirmed that the SETD8 mutants lose the methyltransferase activity on H4K20 substrate. The RNA-seq data in the context of SETD8 mutant indicated that the c-Myc pathway was upregulated without affecting c-Myc expression. With the technology of Bioorthogonal Profiling of Protein Methylation (BPPM), we have found that SETD8 can methylate cancer-associated transcription factors in a cellular context. Collectively, these findings suggest that native SETD8 can act on cancer driving-associated transcription factors and its mutant maintains this methyltransferase activity but spare H4K20 methylation for cancer malignancy.
Acknowledgements: This project was supported by 1R01GM120570.
Citation Format: Yongxia Zhu, Lihui Wang, Chamara Senevirathne, Shi Chen, Fabio Pittella Silva, Minkui Luo. Using cancer-associated variants to dissect functions of SETD8 [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 353.
Abstract 3533: Elevated expression of heme related proteins in viable tumor cells treated with vascular disrupting agent, combretastatin A-4 phosphate in xenograft models of NSCLC
Authors: Dey Sanchareeka , Kumari Sharda , Kalainayakan Sarada Preeta , Ghosh Poorva , Zhang Li , Liu Li 
Published: August 2018

Abstract
Tumors cannot grow without a supply of oxygen and nutrients. Hence, targeting tumor vasculature with Vascular Disrupting Agents (VDAs) represents a promising therapeutic strategy, especially for the treatment of solid tumors. However, VDAs cause central necrosis, leaving a rim of viable tumor cells that often eventually lead to tumor recurrence and development of resistance. Here, we aim to better understand the underlying molecular mechanisms leading to the acquisition of VDA-resistance and its correlation with the extent of hypoxia and respiratory functions.
A well-known VDA, Combretastatin A-4 phosphate (CA4P), was used for the study. First, a NSCLC cell line expressing luciferase was implanted into the right flanks of female SCID mice. Next, CA4P was administered intraperitoneally. The effect was monitored 3 and 24 hours post injection of CA4P through BLI (Perkin Elmer's IVIS Lumina III) after subcutaneous injection of luciferin. After sacrificing the mice, the tumors were harvested, formalin-fixed, and paraffin-embedded for Immunohistochemistry (IHC).
Our BLI data indicated significant decrease in radiance 3 hour post treatment (total flux in photons per second) which remained so at 24 hours, when luciferin was re-administered. Our IHC data indicated enhanced levels of enzymes involved in heme biosynthesis, uptake and degradation, and hemoproteins involved in oxidative phosphorylation. Furthermore, we examined the effect of a mitochondrial targeting agent (MTA) that undermined the expression of these proteins, on the progression of subcutaneous tumor xenografts.
Citation Format: Sanchareeka Dey, Sharda Kumari, Sarada Preeta Kalainayakan, Poorva Ghosh, Li Zhang, Li Liu. Elevated expression of heme related proteins in viable tumor cells treated with vascular disrupting agent, combretastatin A-4 phosphate in xenograft models of NSCLC [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 3533.
Abstract 3545: Identifying the effects of lung cancer exosomes on non-tumorigenic human bronchial epithelial cells
Authors: Kubo Hana , Humphrey Sean E. , Kitdumrongthum Sarunya , Tian Feng , Allen Sarah , Kasinski Andrea L. 
Published: August 2018

Abstract
Lung cancer is the leading cause of death from cancer in most industrialized countries and many lung cancer patients remain undiagnosed until the development of locally advanced or metastatic lung cancer. Despite extensive research, universal biomarkers for the early diagnosis of lung cancer remain elusive, and therapies for treating lung cancer patients remain ineffective and unfocused. This makes the identification of new diagnostic biomarkers and therapeutic targets for the treatment of lung cancer a critical need for patients. Exosomes, nanovesicles secreted by a variety of cell types, are known to transfer bioactive molecules such as proteins and nucleic acids that induce physiological changes in recipient cells. Exosomes secreted by cancer cells have been shown to promote tumor initiation, progression, and metastasis in various cancer types, but have been understudied in lung cancer. Our study aims to identify the effects lung cancer secreted exosomes may have on non-cancerous cells of the tumor microenvironment by assessing their tumorigenic effects on normal lung epithelial cells. To that end, we treated normal lung epithelial cells with exosomes derived from a panel of human non-small lung cancer cell lines. Treated cells acquired the ability to invade and migrate. As a proxy for metastasis, cancer exosomes are also being assayed for their ability to permeabilize a monolayer of normal lung epithelial cells. Further assessing the molecules within cancer exosomes critical for promoting these oncogenic behaviors in non-tumorigenic cells could lead to the discovery of potential diagnostic biomarkers and therapeutic targets for inhibiting tumor growth in affected patients.
Citation Format: Hana Kubo, Sean E. Humphrey, Sarunya Kitdumrongthum, Feng Tian, Sarah Allen, Andrea L. Kasinski. Identifying the effects of lung cancer exosomes on non-tumorigenic human bronchial epithelial 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 3545.
Abstract 3547: Properties of lipid rafts in two epigenetically distinct subtypes of the oncogenic cell-line SW13
Authors: Espejo Luis , Leyva Kathryn J. , Hull Elizabeth E. 
Published: August 2018

Abstract
The epithelial SW13 cancer cell line has two naturally occurring well-defined cell subtypes. The SW13(Vim-) has a phenotype that resembles typical epithelial tumors, displaying increased growth and proliferation with a low level of invasiveness. The SW13(Vim+) subtype has a mesenchymal-like phenotype, commonly associated with more invasive and metastatic states of epithelial cancers. SW13(Vim-) can be converted to a pseudo SW13(Vim+) phenotype when treated with histone deacetylase inhibitors (HDACi). This model is used to study the epigenetic phenotypic differences between tumor-like cancer cells and cells that display a more metastatic phenotype. Gene chip data obtained from the SW13 treated and untreated cells displays differential expression in many genes, specifically genes for cellular membrane proteins and genes involved in cholesterol, sphingolipid, and GPI-anchored protein metabolism; all of which are essential components of lipid rafts. Additionally, recent improved outcomes noted in patients using statin drugs further implicates that cholesterol plays a role in cancer progression, although the mechanism for this improvement is not well understood. This suggests lipid rafts are a candidate for a physical structure that manifests the differential effect of cholesterol perturbations in cancer phenotypes. We hypothesize that lipid raft protein composition is distinctly different between the two SW13 cell subtypes, and that the differences in the composition of lipid rafts may play a role in the unique oncogenic phenotypes of the two subtypes. Utilizing low-temperature detergent-resistant lipid raft isolation techniques, western blotting, and mass spectrometry we investigate protein composition differences between the two SW13 cell subtypes. Cholesterol assays are applied to assess the distribution and total cholesterol content of each SW13 subtype, this also provides translational confirmation of the gene chip data obtained from the subtypes. Cholesterol depletion techniques utilizing cyclodextrin for acute disruption and simvastatin for chronic disruption are being implemented to perturb lipid rafts and observe their role in the oncogenic phenotypes of the SW13 cell subtypes. Specifically, metastatic qualities are measured after lipid raft and cholesterol perturbations. Initial findings support differential cholesterol representation in the two SW13 cell subtypes. Potential findings may explain a mechanism in which cholesterol perturbations are capable of decreasing metastasis and improving the outcome of patients with epithelial cancers.
Citation Format: Luis Espejo, Kathryn J. Leyva, Elizabeth E. Hull. Properties of lipid rafts in two epigenetically distinct subtypes of the oncogenic cell-line SW13 [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 3547.