tbuckley/cabot-search huggingface dataset:
Abstract LB-333: Lymphatic endothelium increases antioxidant capacity of triple-negative breast cancer cells and protects from cell death
Authors: Mirela Berisa, Simona Podgrabinska, Jerry Chipuk, Mihaela Skobe
Journal: Cancer Research (2017)

Abstract Involvement of lymphatic system with cancer and the extent of lymph node metastases are directly correlated with the poor patient outcome. However, it is not understood whether the presence of lymphatic metastases is only indicative of an aggressive cancer or if the lymphatic vessel microenvironment directly contributes to the metastatic progression. We demonstrate that soluble factors produced by lymphatic endothelial cells (LECs) protect triple negative breast cancer cells from cell death in vitro. Co-culture with LECs or LEC-conditioned medium (LEC-CM) protected cancer cells from death induced by the loss of homotypic cell adhesion, nutrient deprivation, or loss of matrix attachment. High levels of reactive oxygen species (ROS) preceded cell death, and were significantly decreased in tumor cells upon treatment with LEC-CM. Furthermore, LEC-CM protected tumor cells from death induced by exogenous oxidative stress (H2O2), while treatment with the anti-oxidant N-acetyl-cysteine (NAC) recapitulated the cytoprotective effect of LEC-CM. RNA-Seq analysis revealed Nrf2 pathway as the most upregulated stress-pathway induced in tumor cells upon loss of adhesion. Nrf2 and other stress signaling pathways were significantly diminished in the presence of LEC-CM. Pharmacological inhibition of the pentose phosphate pathway (PPP) and the components of thioredoxin and glutathione scavanging systems increased ROS and cell death in LEC-CM indicating that the maintenance of redox homeostasis and cell viability by LEC-CM is dependent on the PPP pathway and in particular thioredoxin system. Furthermore, LEC-CM preserved integrity and function of mitochondria. These results demonstrate that soluble factors produced by lymphatic endothelium promote survival of triple-negative breast cancer cells under stress by regulating tumor cell redox homeostasis and promoting mitochondrial function. Citation Format: Mirela Berisa, Simona Podgrabinska, Jerry Chipuk, Mihaela Skobe. Lymphatic endothelium increases antioxidant capacity of triple-negative breast cancer cells and protects from cell death [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 LB-333. doi:10.1158/1538-7445.AM2017-LB-333
Abstract 3327: Sortilin controls the EGFR nuclear translocation
Authors: Hussein Al Akhrass, Thomas Naves, Marie-Odile Jauberteau, François Vincent, Fabrice Lalloué
Journal: Cancer Research (2017)

Abstract The epidermal growth factor receptor (EGFR) deregulations play a central role in cancer progression. EGFR generates extra- and intracellular signals through various pathways, including its release in the tumor microenvironment through extracellular vesicles, as well as the nuclear EGFR signaling. That ultimately results in oncogenic signals promoting the tumor aggressiveness. Our previous report showed that sortilin, a member of the VPS10P sorting proteins, is associated with EGFR to allow its secretion through exosomes in non-small cell lung cancer (NSCLC) cells. Furthermore, sortilin is mainly present in the Golgi which is an essential compartment involved in the EGFR bypass towards the nucleus. Therefore, our aim is to investigate the potential role of sortilin in EGFR nuclear translocation. EGFR and sortilin translocation into the nucleus has been validated by proximity ligation assay and confocal microscopy analysis. Moreover, to study the sortilin function in the EGFR nuclear translocation, we resorted to the NSCLC cell line A549 in which the sortilin expression was silenced using a shRNA delivery. Subcellular fractionations and nuclear protein extractions were performed to study the impact of the sortilin loss on the EGF-induced EGFR nuclear translocation. EGF stimulation highly increases the nuclear translocation of the EGFR and sortilin complex. Interestingly, sortilin depletion significantly decreases the EGF-induced EGFR nuclear translocation in the A549 cells. Strikingly, sortilin-depleted cells exhibit an overexpression of EGFR target genes (MYC, ABCG2, AURKA and CCND1) compared to the control cells. These results suggest that the overexpression of the EGFR target genes is independent of EGFR nuclear translocation in sortilin-depleted cells. Thus, we analyze the activation of the known transcription factors directly involved in the control of EGFR up-regulated genes to determine whether they are activated in sortilin-depleted cells. Moreover, to better understand the sortilin-dependent EGFR nuclear translocation, we compare functional properties (proliferation, migration and angiogenesis assays) of sortilin-depleted and control cells. Altogether, our findings suggest a key role of sortilin in the regulation of the EGFR nuclear transport, towards the control of target genes that are widely involved in cancer progression. Citation Format: Hussein Al Akhrass, Thomas Naves, Marie-Odile Jauberteau, François Vincent, Fabrice Lalloué. Sortilin controls the EGFR nuclear translocation [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 3327. doi:10.1158/1538-7445.AM2017-3327
Abstract 3305: Autophagic induction through upregulation of sestrin-2 transcription and mRNA stability mediates the anticancer effect of new compound ChlA-F
Authors: Xiaohui Hua, Chuanshu Huang, Xueru Wu, Jingxia Li
Journal: Cancer Research (2017)

Abstract ChlA-F is a novel conformation-derivative of Cheliensisin A (Chel A), which is a new styryl-lactone isolated from Chinese Herb Goniothalamus cheliensis Huand shows potent antitumor potential effect both in vitro and in vivo. However, the anticancer activity and its potential mechanisms underlying ChlA-F action have never been explored. In present study, we evaluated the potency of ChlA-F on anchorage-independent growth and its association with autophagic responses in human high grade invasive bladder cancer cells. We found that ChlA-F significantly inhibited anchorage-independent growth of human bladder cancer cells by induction of autophagy in a sestrin2(SESN2)-dependent Fashion. Our results revealed that ChlA-F treatment specifically induced SESN2 expression via increasing its both gene transcription and mRNA stability. On the one hand, ChlA-F treatment markedly attenuated Dicer protein abundance, and in turn abolished miR-27a maturation and further relieved miR-27a directly binding to SESN2 mRNA 3’UTR, thereby promoting SESN2 mRNA stabilization. On the other hand,ChlA-F treatment promoted Sp1 abundance and consequently mediated SESN2 transcription. Moreover, either knockdown of Sp-1 or ectopic expression of miR-27a could abolish the autophagic response and reversed the inhibition of anchorage-independent growth in human bladder cancer cells. These results demonstrate that anticancer effect of ChlA-F is mediated by its activating autophagic pathway through promoting both SESN2 mRNA transcription and stabilization,which offers novel insights into the anticancer effect of ChlA-F on bladder cancer and provides a therapeutic alternative against human bladder cancer. Citation Format: Xiaohui Hua, Chuanshu Huang, Xueru Wu, Jingxia Li. Autophagic induction through upregulation of sestrin-2 transcription and mRNA stability mediates the anticancer effect of new compound ChlA-F [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 3305. doi:10.1158/1538-7445.AM2017-3305
Abstract 2605: Improving data quality in oncology immunotherapy clinical research by big data analytics and data visualization
Authors: Chengsen Xue, Joanne Cuomo, Walter Meyers, Thomas W. Mc Closkey
Journal: Cancer Research (2017)

Abstract Flow cytometric assessment of cellular and intracellular biomarkers facilitates the development of new classes of cancer immunotherapy therapeutics. This powerful tool has multiple applications including 1) detecting PD1, PDL-1 and caspase-3 for apoptosis, 2) isolating, defining, and quantifying dendritic cells and their intracellular cytokine profile, 3) immunophenotyping subpopulations of B, T, NK, regulatory T, and helper T cells, and, 4) using tetramer analysis to detect and monitor the frequency of antigen-specific cytotoxic T lymphocytes (CTL). However, lack of knowledge of normal distributions and standard ranges for the esoteric reportables generated by flow cytometry is one of the most challenging problems in this promising field. Here we describe a new method to improve data quality in clinical research by big data analytics and data visualization. Each data point was tagged. By applying a simple statistical analysis, a self-defined range allowed all of the outlier numbers to be identified. By repeating this process, clear patterns emerged, and all questionable data points were marked. In addition, the system can differentiate biodiversity in subjects from a more homogenous population, which can be exploited further for the purpose of personal and precision medicine. Other benefits of the new system are to predict the outcome of the clinical study and to generate new clues in the understanding of the underlying biological mechanisms. Big data analytics and data visualization show unparalleled advantages in oncology studies through simultaneously monitoring unlimited data points related to surface and intracellular biomarkers. It opens a new avenue in cost saving for long, time-consuming clinical trials by using all available data to detect a status change of the immune system. With the improvement of data quality, big data analytics has become an essential tool and an integrated part of cancer immunotherapy and the development of cancer vaccines. Citation Format: Chengsen Xue, Joanne Cuomo, Walter Meyers, Thomas W. Mc Closkey. Improving data quality in oncology immunotherapy clinical research by big data analytics and data visualization [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 2605. doi:10.1158/1538-7445.AM2017-2605
Abstract 4814: Testing personalized therapies for ovarian cancer using mate pair genomic analysis and patient-derived xenografts
Authors: Konstantinos Leventakos, Faye R. Harris, Lin Yang, Xiaonan Hou, Saravut Weroha, Irina V. Kovtun
Journal: Cancer Research (2017)

Abstract Purpose: The treatment of ovarian cancer poses a challenge since 70% of patients will relapse with incurable platinum resistant disease. Although ovarian cancers lack frequently-occurring driver mutations or amplifications, the study presented herein examines the concept of individualized therapy based on mate pair sequencing and protein expression in ovarian cancer patient-derived xenografts. Experimental Procedure: Macrodissection of patient tumor was followed by genomic DNA isolation and next-generation sequencing using an Illumina Mate Pair protocol to identify structural genomic changes and copy number variations. Secondary analyses were carried out to select potential therapeutic targets among those. The tumors were also propagated intraperitoneally in immunocompromised mice and treated with standard chemotherapy or/and targeted therapy chosen based on genomic analyses. Results: Mate pair analysis revealed that, in general, copy number changes (amplifications, gains and losses) were common in ovarian tumors and included genes potentially targetable. Tumors from early generation patient- derived xenografts showed a landscape of genomic aberrations identical to that of original patient tumor. One PDX model in which high expression of HER2 and copy number gains at RICTOR and AKT genetic loci were revealed, was treated with either chemotherapy and Pertuzumab/trastuzumab (HER2 inhibitors), MK-8669 (mTOR inhibitor) or MK-2206 (AKT inhibitor) or chemotherapy alone. Tumor size was measured by serial abdominal ultrasound and after 28 days, the final tumor size ratio compared to baseline was 0.23, 0.36, 0.55 and 0.56, respectively, indicating that the best response was seen in the combined chemotherapy and Pertuzumab/trastuzumab cohort and that was better than in the chemotherapy only cohort. Conclusions: Patient-derived xenografts models in conjunction with genomic and protein analyses of patient tumors are valuable for testing of combination therapies including specific targeting drugs. This approach also provides actionable information for more tailored treatment of ovarian cancer patients. Citation Format: Konstantinos Leventakos, Faye R. Harris, Lin Yang, Xiaonan Hou, Saravut Weroha, Irina V. Kovtun. Testing personalized therapies for ovarian cancer using mate pair genomic analysis and patient-derived xenografts [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 4814. doi:10.1158/1538-7445.AM2017-4814
Abstract LB-318: Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation
Authors: Raquel Torres-Guzmán, Carmen Baquero, Carlos Marugan, Cecilia Mur, Severine I. Gharbi, Sandra Gomez, Joaquín Amat, Karsten Boehnke, Philip W. Iversen, Alfonso deDios, Xueqian Gong, Sean Buchanan, Richard P. Beckman, Maria José J. Lallena
Journal: Cancer Research (2017)

Abstract Lung cancer is the most common tumor cancer worldwide and approximately 15-25% of the patients with lung adenocarcinoma have KRAS driven tumors. These malignancies involve, in the majority of cases, a constitutive activation of KRAS signaling pathway (1,2) and are associated with poor prognosis in patients with advanced disease (metastatic setting). Currently there is no specific therapy to target KRAS driven tumors approved by FDA (3), then finding alternative targeted therapies is a need to cover for this disease. Pharmacological inhibition of CDK4 was been suggested as a beneficial therapy to treat NSCLC patients carrying K-RAS oncogenes; and researchers base the potential efficacy of this approach on a synthetic lethal interaction between K-ras and CDK4 in in this type of tumors (4). Hence, CDK4/6 inhibitors appear as promising therapy to treat this type of tumors. Abemaciclib is a cell cycle inhibitor with selective activity against CDK4 and CDK6 and is being evaluated in advanced clinical trials for its potential to reduce NSCLC cancer growth. Here we describe studies towards the in-vitro mechanism of action of abemaciclib to reduce tumor cells growth in NSCLC cell lines harboring mutations in KRAS. Overall, abemaciclib reduces NSCLC cell growth as indicated by a reduction of cell number and proliferation biomarker Ki67 upon treatment. This tumor growth inhibition is mediated by arrest of cell cycle in G1 phase as a direct consequence of Rb phosphorylation blockade. In this study we are further reporting a phenotypic characterization of sensitive cell lines monitoring cell proliferation, senescence, and apoptosis markers using flow cytometry and high content imaging approaches as well as metabolic profiling. . Bibliography (1) Schubbert S, Shannon K and Bollang G (2007) Nature Rev. Cancer 7(4) 295-308. (2) Ihle NT et al (2012) J Natl Cancer Inst. 104(3): 228-239. (3) Roberts PJ et al (2010) J Clin Oncol. 28(31):4769-77 (4) Puyol M et al (2010) Cancer Cell 1(13): 63-73. Citation Format: Raquel Torres-Guzmán, Carmen Baquero, Carlos Marugan, Cecilia Mur, Severine I. Gharbi, Sandra Gomez, Joaquín Amat, Karsten Boehnke, Philip W. Iversen, Alfonso deDios, Xueqian Gong, Sean Buchanan, Richard P. Beckman, Maria José J. Lallena. Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation [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 LB-318. doi:10.1158/1538-7445.AM2017-LB-318
Abstract 3184: Autophagy regulation by vacuolar-ATPases: A contributing mechanism of chemo-resistance in ovarian cancer
Authors: Arpita Kulshrestha, Gajendra K. Katara, Safaa A. Ibrahim, Alice Gilman-Sachs, Kenneth D. Beaman
Journal: Cancer Research (2017)

Abstract In ovarian cancer (OVCA), the main obstacle in the clinical usefulness of platinum based drugs is the eventual emergence of chemo-resistant tumors. Exposure of cancer cells to platinum drugs such as cisplatin elicits a stress response that leads to the induction of coping mechanisms favoring cancer cell survival. Autophagy induction is the primary protective mechanism in cancer cells that also contributes to cisplatin resistance. A tightly regulated pH is imperative for autophagy and the role of major pH regulators is therefore vital to this process. Vacuolar ATPases (V-ATPases) are the multi-subunit proton pumps that regulate intra/extra-cellular pH in cancer. Its `a2` isoform (V-ATPase-a2) is located at the plasma membrane and early/late endosomal compartments. We previously found that this isoform is overexpressed on cisplatin resistant cells (cis-R) and its inhibition sensitizes cis-R cells to platinum drugs. In continuation with our efforts, the present study was performed to understand what alterations in the autophagy process occur upon V-ATPAse-a2 inhibition and how these contribute to cisplatin sensitization. Expression profiling of ovarian cancer cells lines (A2780-cis R and TOV-112D- cis R) revealed that upon a2 inhibition, the basal levels of autophagosome membrane protein, LC3B were enhanced compared to control cis-R cells as determined by flow cytometry and western blot analysis. Upon cisplatin treatment, the LC3B levels were further enhanced in a2 inhibited cis-R cells compared to control cells. Further, we observed a significantly increased expression of the autophagy protein, beclin-1 in these cells as compared to control cells. In addition, the inhibition of V-ATPase-a2v increased the protein levels of SQSTM1/p62, a known substrate for the autophagy process. The enhanced LC3B and P62 levels suggest an accumulation of the autophagosomes due to an altered autophagy flux upon V-ATPase-a2v inhibition. The study provides a rationale for the utility of V-ATPase-a2 inhibitors in combination with standard drugs as a novel strategy to improve the treatment efficacy of the chemoresistant ovarian cancer. Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Safaa A. Ibrahim, Alice Gilman-Sachs, Kenneth D. Beaman. Autophagy regulation by vacuolar-ATPases: A contributing mechanism of chemo-resistance in ovarian 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 3184. doi:10.1158/1538-7445.AM2017-3184
Abstract 925: Tumorigenesis of murine iPS cell is prevented by iron depletion with downregulation of stemness markers
Authors: Yuki Katsura, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Takayuki Ninomiya, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2017)

Abstract Background: Iron plays a crucial role in the various metabolic pathways and it is essential for life. However excess of iron is known to cause cancer. There are many reports that iron depletion treatment indicates antitumor effect. Previously, we have confirmed that iron depletion treatment indicates antitumor effect against Cancer stem cell (CSC) model, miPS-LLCcm, which was converted from murine induced pluripotent stem cell (miPS cell) in Okayama university (Chen at el. PLOS ONE 2012), and also suppresses CSC markers. Many tumors contain phenotypically and functionally heterogenous cancer cells due to pluripotency of CSC. Although there are various theories about the origin of CSC, miPS has a pluripotency and regarded as the top of the hierarchy, it can be the candidate of the origin of CSC. miPS cell is known to form teratoma when inoculated into nude mouse because of its undifferentiated status. We hypothesized if we could suppress the stemness and tumorigenicity of miPS cell by iron depletion treatment, it can be applied to the therapy for CSC and undifferentiated status cancer cell. In this study, we investigated the stemness and tumorigenecity of miPS cell with iron depletion treatment. Methods: We used miPS cell(cell name : iPS-MEF-Ng-20D-17) purchased from Riken Cell Bank(Japan). Deferasirox (DFX), an popular commercial available oral iron chelator was used for iron depletion treatment. Western blot analysis was done to examine the expression of the stemness markers including Nanog, Oct3/4, Sox2, Klf4, c-Myc. Subcutaneous model of miPS cell and miPS cell treated with DFX (50μM) were used in vivo study. Tumors were harvested for immunohistochemistry. Results: Stemness markers of miPS cell were suppressed strongly by DFX in western blot analysis. DFX also suppressed the subcutaneous tumor growth. The average tumor volume of the control group was 665.3±430.8mm3 while that of the DFX treated group was 204.3±76.2 mm3(p&amp;lt;0.05) on day 20. Immunohistochemistry of the tumor revealed the suppression of the stemness markers in the DFX treated group compared with the control group. Citation Format: Yuki Katsura, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Takayuki Ninomiya, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Tumorigenesis of murine iPS cell is prevented by iron depletion with downregulation of stemness markers [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 925. doi:10.1158/1538-7445.AM2017-925