bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5873: Chaetocin sensitizes GBM cells to TRAIL and BH3 mimetics induced apoptosis
Authors: Özyerli Ezgi , Yeşil Zeynep Kahya , Oppermann Udo , Önder Tuğba Bağcı 
Published: July 2017

Abstract
Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor, which lacks efficient therapy. TRAIL is an antitumor agent that triggers apoptosis selectively on tumor cells, thus can be utilized as therapeutic approach for GBM. However, most GBM cells confer TRAIL resistance and how this resistance is regulated at a molecular level is not completely clear. Epigenetic deregulation has been increasingly recognized as a hallmark of cancer. In this study, we conducted a drug screen against selected chromatin modifiers in U87MG GBM cells and identified Belinostat, Trichostatin A and Chaetocin as potential apoptosis regulators. While Belinostat and Trichostatin A are well-characterized histone deacetylase inhibitors in the context of malignancies, Chaetocin’s role in cancers is less well-known and its relation to TRAIL is novel. Chaetocin is a fungal mycotoxin that inhibits Suv39H1, a histone methyltransferase (HMT) that catalyzes H3K9 methylation. In this study, we investigated how Chaetocin affects the response of GBM cells to apoptotic stimuli by TRAIL. To this end, GBM cell lines U87MG and U373 are treated with varying dose of Chaetocin and cells’ viability and apoptosis responses to varying doses of TRAIL are analyzed. Chaetocin decreased viability down to 11% of control in U87MG cells upon TRAIL treatment, without inducing cellular toxicity and apoptosis by itself. Chaetocin was shown to upregulate the expression of proapoptotic genes while downregulating antiapoptotic gene expression. In addition, elevated Caspase3/7, Caspase8 and Caspase9 activities were detected in U87MG upon Chaetocin treatment together with PARP cleavage as indicator of apoptosis. Chaetocin also sensitized GBM cells to BH3 mimetic ABT263 which indicates that sensitization of GBM cells by Chaetocin is not limited to TRAIL but is rather a general phenomenon for apoptosis. We infer from these findings that Chaetocin plays critical and specific role in apoptotic pathway. Our future work is directed towards examining the changes in gene expression profiling of GBM cells upon Chaetocin treatment and understanding the functional role of H3K9 Methylation in GBM cell apoptosis. To this end, RNAseq analysis is currently being performed and expected to enlighten Chaetocin’s mechanism of action. These findings support our motivation that identifying epigenetic modifier drugs as apoptosis sensitizer may be a promising therapeutic approach for GBM treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Ezgi Özyerli, Zeynep Kahya Yeşil, Udo Oppermann, Tuğba Bağcı Önder. Chaetocin sensitizes GBM cells to TRAIL and BH3 mimetics induced apoptosis [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 5873. doi:10.1158/1538-7445.AM2017-5873
Abstract 5875: Schlafen 11 (SLFN11) induces lethal S-phase arrest in response to DNA damage: A novel mechanism of how cancer cells are killed by DNA damaging agents
Authors: Murai Junko , Pommier Yves 
Published: July 2017

Abstract
The putative DNA/RNA helicase, Schlafen 11 (SLFN11), is a recently discovered determinant of sensitivity to DNA damaging agents such as platinums, topoisomerase I and II inhibitors (camptothecins, etoposide, doxorubicin), cisplatin, gemcitabine (1-3) and PARP inhibitors (olaparib, talazoparib) (4). Because SLFN11 expression is suppressed in ~45% cancer cell lines, SLFN11 inactivation is potentially one of the most prevalent mechanisms of resistance to DNA damaging agents. However, the molecular mechanisms of SLFN11 action in the DNA damage response have not been solved. Using isogenic cell lines of SLFN11-knockout and SLFN11-overexpression, we will show that SLFN11 binds to chromatin in response to camptothecin within 2 hours. ChIP-seq analysis reveals that SLFN11 preferentially binds to replication origins under camptothecin treatment. We identify two helicases DHX9 and MCM3, which are involved in replication and origin firing, as binding partners of SLFN11 by IP-MS analysis. Cell cycle analyses revealed that SLFN11 inhibits replication in response to camptothecin, which irreversibly lasts until apoptosis is exerted. Notably, the S-phase arrest by SLFN11 is independent of ATR-mediated S-phase checkpoint. Unscheduled origin firing by ATR inhibition under camptothecin treatment is suppressed in the presence of SLFN11. Hence, SLFN11 enforces irreversible S-phase arrest in damaged cells possibly by inhibiting dormant origin firing and inactivating the MCM helicase in conjunction with DXH9. We conclude that the irreversible S-phase arrest by SLFN11 leads to cell death in response to DNA damaging agents, which is a novel mechanism of how cancer cells are killed by DNA damaging agents.
1.
Sousa FG, Matuo R, Tang SW, Rajapakse VN, Luna A, Sander C, et al. Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity. DNA Repair (Amst) 2015;28:107-15.
2.
Zoppoli G, Regairaz M, Leo E, Reinhold WC, Varma S, Ballestrero A, et al. Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc Natl Acad Sci U S A 2012;109(37):15030-5.
3.
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 2012;483(7391):603-307.
4.
Murai J, Feng Y, Yu GK, Ru Y, Tang SW, Shen Y, et al. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 2016.
Citation Format: Junko Murai, Yves Pommier. Schlafen 11 (SLFN11) induces lethal S-phase arrest in response to DNA damage: A novel mechanism of how cancer cells are killed by DNA damaging agents [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 5875. doi:10.1158/1538-7445.AM2017-5875
Abstract 5879: Establishing doxorubicin resistant HCC1806 triple negative breast cancer cell lines result in the differential expression of let7a and miR34a
Authors: Rorie Checo J. , Moses Malcolm M. , Musa Mohammed K. , Godfrey Sherette S. 
Published: July 2017

Abstract
Resistance to chemotherapy is one of the major difficulties in the treatment of triple negative breast cancer. Besides the typical known causes of drug resistance, tumor microenvironment can also promote resistance by preventing the drug from accumulating in tumor cells in order to elicit a cytotoxic response. TNBC is characterized by the loss or low expression of estrogen receptor, progesterone receptor, and HER2 proteins that have been targeted and established as somewhat effective therapy regiments in other breast cancer subtypes including liminal breast cancer. Since TNBC tumors are missing these well-known drug targets, there is little to no advancement in the establishment of drug therapies to accurately target this breast cancer subtype. TNBC is termed as aggressive due to the fact of its invasiveness and metastatic properties. One potential mediator of TNBC aggressive behavior may be due to the fact that this breast cancer subtype may have as high as an 80% p53 tumor suppressor gene mutation rate which may also play a role in the ability of TNBC to recur as a result of the inability to kill all remaining TNBC cells leading to chemotherapy resistance. In these studies, we hope to mimic TNBC recurrence by establishing doxorubicin resistant HCC1806 TNBC cell lines. Here we show that we were able to sustain TNBC cell growth after pulse treatments with increasing concentrations of doxorubicin, and we revealed that p53-related miRNAs, let7a and miR34a, were differentially expressed after pulse treating the HCC1806 cells. Understanding the molecular and mechanistic factors related to recurrence and doxorubicin-resistance in HCC1806 cells may help to develop a list of possible targets for molecular therapy to overwhelm tumor drug resistance in triple negative breast cancer and may develop or establish a list of potential targets for disabling, or combating resistance to doxorubicin treatment in TNBC patients.
Note: This abstract was not presented at the meeting.
Citation Format: Checo J. Rorie, Malcolm M. Moses, Mohammed K. Musa, Sherette S. Godfrey. Establishing doxorubicin resistant HCC1806 triple negative breast cancer cell lines result in the differential expression of let7a and miR34a [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 5879. doi:10.1158/1538-7445.AM2017-5879
Abstract 5882: FAK is required for the survival of tumor cells in MMTV-Wnt1 driven basal-like mammary tumors
Authors: Paul Ritama , Yeo Syn K. , Luo Ming , Waltz Susan , Guan Jun-Lin 
Published: July 2017

Abstract
Breast cancer is a heterogeneous disease. Stratification of patients based on the subtype of breast cancer is a key to successful treatment of breast cancer. Focal Adhesion Kinase (FAK), a cytoplasmic tyrosine kinase is over expressed and activated in several cancers including breast cancer. Our earlier studies have shown inhibition of FAK in MMTV-PyMT mouse mammary tumors that are classified as Luminal B subtype, delays tumor onset and reduces tumor growth. To address whether inhibition of FAK would be beneficial in basal-like mammary tumors, we generated a conditional deletion of FAK and a knock in mutation of FAK lacking its kinase activity, in MMTV-WNT1 mouse model, which classifies as basal-like. Similar to PyMT mammary tumors we found that loss of FAK or its kinase function delays tumor onset and tumor growth of basal like WNT1 mammary tumors. However unlike the PyMT tumors, the reduced tumor growth in WNT1 model is not due to decreased proliferation. Interestingly loss of FAK activity in WNT1 tumors results in accumulation of cleaved caspase 3, suggesting that loss of FAK activity results in compromised tumor cell survival. When we investigated the pathways through which FAK could affect survival, we found that loss of FAK activity reduces activation of AKT. Reduced AKT activation induces the expression of pro-apoptotic genes. In summary our studies show that in a basal-like tumor model, FAK is required for survival of the tumor cells. Hence inhibition of FAK could be beneficial for elimination of basal-like tumor cells.
Citation Format: Ritama Paul, Syn K. Yeo, Ming Luo, Susan Waltz, Jun-Lin Guan. FAK is required for the survival of tumor cells in MMTV-Wnt1 driven basal-like mammary tumors [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 5882. doi:10.1158/1538-7445.AM2017-5882
Abstract 5883: CHD1 as regulator of cell adhesion in Ets fusion negative prostate cancer
Authors: Kareddula Aparna , Petrosky Whitney , Tereshchenko Irina , Medina Daniel , Aviv Hana , Singer Eric , DiPaola Robert S. , Hirshfield Kim M. 
Published: July 2017

Abstract
Prostate cancer (PCa) develops into lethal disease in about 10% of men diagnosed with this malignancy.
Common genomic changes are seen in PCa such as alterations in CDKN1B, RB1, TP53, PTEN, NKX3-1, MYC and androgen receptor.
Oncogenic fusions involving the Ets family are seen in 50-70% PCa patients, the most common of which is TMPRSS2-ERG. TMPRSS2-ERG influences cell migration, particularly when PTEN is co-deleted or PIK3CA activating mutations are present. However, in the absence of ERG fusions, molecular drivers of the PCa phenotype are less clear but include alterations in SPOP (6-15% of PCa), SPINK1 (10%), MAP3K7 (18-38%) and CHD1 (15-27%).
CHD1 (Chromo-domain Helicase DNA Binding Protein-1) is a chromatin remodeling factor with many roles including homologous recombination mediated DNA repair of double strand breaks and maintenance of genomic stability and therefore it is hypothesized to cause the predominant intrachromosomal rearrangements observed in Ets fusion negative tumors. This study was undertaken to evaluate the cellular effects that follow CHD1 deletion that could aid PCa initiation and progression. CHD1 was knocked out in the non tumorigenic, HPV16 immortalised prostate epithelial cell line, RWPE-1, using CRISPR/Cas9. Compared to parental RWPE-1 and non target cells (NT2), the CHD1 KO cells had a smaller and rounder morphology and were less adherent to tissue culture plates. To study expression of extracellular matrix and adhesion molecules, RT profiler assay was performed using RWPE-1 parental and CHD1 KO cells. CHD1 KO cells showed a decrease in the expression of SPARC, MMP2, ITGA2, ITGA5, ITGA6, FN1, LAMB3, collagen,
tenascin and vitronectin as compared to parentals and NT2. Reduction in extracellular matrix and adhesion molecules and altered morphology of CHD1 KO cells as compared to parentals and NT2 cells suggest that loss of CHD1 reduces cell-cell and cell-matrix adhesion.
These results suggest that in the absence of PTEN loss in Ets negative tumors, deletion of CHD1 gene could change cell adhesion dynamics ascribing a new role for CHD1 in the development and progression of PCa.
Citation Format: Aparna Kareddula, Whitney Petrosky, Irina Tereshchenko, Daniel Medina, Hana Aviv, Eric Singer, Robert S. DiPaola, Kim M. Hirshfield. CHD1 as regulator of cell adhesion in Ets fusion negative 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 5883. doi:10.1158/1538-7445.AM2017-5883
Abstract 5887: The role of FAK in tumor microenvironment
Authors: Wu Hsin-Jung , Yeo Syn Kok , Wilson Megan 
Published: July 2017

Abstract
Focal Adhesion Kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase important in mediating signal transduction in cell migration, survival and proliferation. Up-regulation of FAK in the tumor cells has been shown to enhance tumor malignancy and correlate with poor prognosis. FAK signaling has also been implicated in impacting tumor microenvironment, including endothelial cells and fibroblasts. However, much less is known about how FAK in the tumor stroma affects tumor progression, or how stromal FAK cross-talks with cancer cells. Here we use an inducible Col1α2-creERT, FAK f/f genetic engineered mouse model (GEMM) to specifically delete FAK in the fibroblasts. Using the GEMM, we found that FAK in stromal fibroblasts facilitates breast tumor growth and metastasis in vivo. We further showed that conditioned media (CM) from human breast cancer cells induced FAK Y397 autophoslphorylation and expression of smooth muscle actin (SMA, a marker for cancer-associated-fibroblasts [CAFs]) of normal human lung fibroblasts. Interestingly, only the breast cancer CM educated fibroblasts, but not the naive un-treated fibroblasts, were able to promote breast cancer cell migration and invasion. Lastly, knockdown of FAK in these “educated” fibroblasts abolished their ability to promote breast cancer cell migration and invasion. Taken together, these data suggest a potential role of stromal FAK in creating a pro-tumorigenic microenvironment for breast cancer development and progression, and provide further rationale in therapeutic benefits of FAK inhibition against various solid tumors.
Citation Format: Hsin-Jung Wu, Syn Kok Yeo, Megan Wilson. The role of FAK in tumor microenvironment [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 5887. doi:10.1158/1538-7445.AM2017-5887
Abstract 5893: Bioenergetic signature from cocultures of pancreatic tumor cell lines and fibroblasts
Authors: Agulló-Ortuño Mª Teresa , Prieto-García Elena , Díaz-García C. Vanesa , Blas Irene Otero , García-Ruíz Inmaculada , López-Martín José A. 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the tumors with greater invasiveness and metastasis. PDAC is associated with a large desmoplastic reaction, characterized by fibroblastic proliferation and extracellular matrix secretion. Besides, cellular bioenergetics has become a central issue of investigation in cancer biology, because the altered energy metabolism of cancer cells has been proposed as a potential target for cancer treatment. We have established co-cultures between PDAC cell lines (Capan-1 or PL-45) and fibroblasts (LC5). A reverse phase protein microarray (RPMA) approach has been applied to quantify proteins of energy metabolism in theses co-cultures, with the aim of identifying potential biomarkers in PDACs. The fifteen proteins of energy metabolism studied included members of the mitochondrial oxidation of pyruvate, the tricarboxylic acid cycle, β-oxidation of fatty acids, electron transport and oxidative phosphorylation, glycogen metabolism, glycolysis and oxidative stress using highly specific antibodies. Co-cultures modified proteins expression of energy metabolism, respect to monocultures. Capan-1 in co-culture increased several proteins belonging to OXPHOS (NDUFS3, SDHB, CORE2 and COXII), the antioxidant SOD2, the mitochondrial HSP60, and G6PDH. The expression of the glycolitic PKM2 decreased. Their fibroblasts partners increased the expression of SDHB and also decreased PKM2. PL-45 in co-culture, experimented an increase in HADHA. Their fibroblasts partners showed a decrease in PKM2, LDHA, IF1, PDHe and HSP60.Capann-1 and PL-45 in co-culture with fibroblast, differ en their energy metabolism phenotype. Overall, the results indicate that the quantification of bioenergetic signature offers potential biomarkers that could be implemented to refine the understanding of the biological principles of PDAC and, eventually, the management of patients with these tumors.
Citation Format: Mª Teresa Agulló-Ortuño, Elena Prieto-García, C. Vanesa Díaz-García, Irene Otero Blas, Inmaculada García-Ruíz, José A. López-Martín. Bioenergetic signature from cocultures of pancreatic tumor cell lines and fibroblasts [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 5893. doi:10.1158/1538-7445.AM2017-5893
Abstract 590: A new standardized CD8 and PD-L1 dual assay
Authors: Monville Florence , Prestat Emmanuel , Yessaad Nadia , Villard Marine , Batista Luciana , Galon Jerome , Adam Julien , Fieschi Jacques 
Published: July 2017

Abstract
PD1/PD-L1 pathway blockade results in a durable clinical response in a fraction of the non-small cell lung cancer (NSCLC) patients. Today, the expression of PD-L1, detected by immunohistochemistry (IHC) at the surface of tumor or tumor-infiltrating immune cells, is used to select patients that may respond to immune checkpoint inhibitors (ICI). However the predictive value of that biomarker alone is questioned. In order to better stratify NSCLC patients, we have developed a new dual-staining IHC assay of PD-L1+ and CD8+ cells (TILs) present in the tumor microenvironment on a single slide prepared from FFPE tissue.
The assay was optimized and fully automated on the Benchmark XT platform (Roche Ventana) with anti-PD-L1 (HDX3) and anti-CD8 (HDX2) monoclonal primary antibodies, respectively revealed with DAB and fast red substrates. Stained slides are analyzed by a pathologist like any other existing IVD test together with the TILs information. In addition, after digitization, the samples are analyzed to quantify brown and red cells with a newly developed digital Pathology (DP) tool.
The following parameters are reported by the DP tool: (1) CD8+ cell density (cells/mm²) ; (2) PD-L1+ cell density (cells/mm²) ; proximity between CD8+ and PD-L1+ cells, either centered on CD8+ or on PD-L1+ cells and finally cluster indexes for CD8+ cells and PD-L1+ cells. HalioDx DP analysis tool can calculate these parameters on any Regions Of Interest (ROI) defined by the user.
Accuracy of the automated numeration of CD8+ and PD-L1+ cells was validated by an expert pathologist. Cell-to-cell distances were validated with an independent DP tool. Variability was assessed for all parameters using adjacent dual-stained slides on complete tissue sections. The concordance with main IVD approved PD-L1 methods was established on a representative set of 55 NSCLC tumours.
HalioDx has developed an innovative assay based on the dual staining of CD8+ and PD-L1+ cells associated to a DP tool to standardize the evaluation of the tumor microenvironment. This assay could have higher predictive performance than existing IVD tests used to identify ICI resistant NSCLC patients.
Citation Format: Florence Monville, Emmanuel Prestat, Nadia Yessaad, Marine Villard, Luciana Batista, Jerome Galon, Julien Adam, Jacques Fieschi. A new standardized CD8 and PD-L1 dual assay [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 590. doi:10.1158/1538-7445.AM2017-590
Abstract 5907: Radiotherapy-induced damage to cancer-associated fibroblasts and its reciprocal influence on cancer progression: Impact of soluble factors
Authors: Wever Olivier De , Tommelein Joke , Bracke Marc , Boterberg Tom , Demetter Pieter , Verset Laurin 
Published: July 2017

Abstract
Preoperative radiotherapy is a mainstay in current management of colorectal cancer. Several tumor types, including colorectal cancer, show an abundant desmoplastic stroma, characterized by cancer-associated fibroblasts (CAFs). Nevertheless the effects of radiation to the CAFs in the stroma and its reciprocal impact on the response of CRC cells to irradiation have not been studied. We investigated the functional (cell number, morphotype) and biochemical (transcriptomics, metabolomics and kinomics) phenotype of CRC cells in response to paracrine signals from irradiated CAFs. Using neutralizing antibodies and small molecule inhibitors, we analysed the role of tyrosine-kinase receptor activation in CRC cells in response to supernatants from irradiated CAFs. Furthermore, the impact of tyrosine-kinase receptor neutralization in combination with RT was evaluated in an orthotopic CRC model. The level of mTOR activation, a downstream tyrosine-kinase receptor intermediate, was analysed in response to neoadjuvant treatment in human CRC specimens. Further work will reveal which soluble factor(s) are implicated in the communication between irradiated CAFs and colorectal cancer cells.
Citation Format: Olivier De Wever, Joke Tommelein, Marc Bracke, Tom Boterberg, Pieter Demetter, Laurin Verset. Radiotherapy-induced damage to cancer-associated fibroblasts and its reciprocal influence on cancer progression: Impact of soluble factors [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 5907. doi:10.1158/1538-7445.AM2017-5907