bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5032: Tumor in a Dish (TiD): Novel approach for precision therapy using patient-derived cells
Authors: Ramamoorthy Prabhu , Thomas Sufi , Ramalingam Sathish , Fnu Gaurav , Sittampalam Sita G. , Jensen Roy A. , Anant Shrikant 
Published: August 2018

Abstract
Metastatic colorectal cancer is a major cause of cancer-related deaths. Most patients with metastatic disease fail to respond to current chemotherapeutic agents. Current, traditional culture model is not appropriate to study the metastatic disease in in vitro condition. Hence, there is an ominous need for developing new therapeutic and preventive agents that can target metastatic cancer. Unfortunately, there are no good in vitro as well as in vivo models available for studying metastatic disease. Hence, in this abstract, we demonstrate the development of a new lung model system, called Primitive Lung in a Dish or PLiD with cancer cells called “Tumor in a Dish” or TiD. The PLiD system shows expression of specific cell type marker like E-cadherin (epithelial cell) vimentin (fibroblast), CD31 (heme-endothelial cells) and LYVE1 (lymph-endothelial cells). Interestingly, we showed expression of lung functional protein like surfactant protein B and D. In the multicell type TiD system, cancer cells were grown in a 3-dimensional (3D) PLiD system containing normal epithelial cells, fibroblasts and endothelial cells. The model resembles in vivo tumor microenvironments, including cell-cell contact, tumor architecture, and the influence of different cell types. We next determined the efficacy of standard colon cancer chemotherapeutic agents. We observed differential activity of 5FU in TiD system when compared to standard 2D and single-cell type 3D cultures. Another surprising result we found was with freshly isolated colon cancer cells from patient samples. Without knowing the genetic characteristics of the cancer tissue, the TiD system was able to identify cells that were resistant to oxaliplatin. Moreover, using this method, we have developed novel drugs that target cancer cells while not affecting the normal tissue. More importantly, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects.
Citation Format: Prabhu Ramamoorthy, Sufi Thomas, Sathish Ramalingam, Gaurav Fnu, Sita G. Sittampalam, Roy A. Jensen, Shrikant Anant. Tumor in a Dish (TiD): Novel approach for precision therapy using patient-derived 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 5032.
Abstract 5051: STAT3 signaling activates MSK1-mediated histone H3 phosphorylation in N-nitrosocompounds induced carcinogenesis
Authors: Qi Hongyan , Yang Zhiyi , Zhang Shuilian , Ke Xinxin , Dai Chujun , Shao Jimin , Shen Jing 
Published: August 2018

Abstract
Signal transducer and activator of transcription (STATs) signaling, particularly STAT3, have been demonstrated to be one of the central pathways for cancer initiation and progression. However, the functional role of STAT3 in regulation of epigenetic changes in cancer, such as histone modifications, remains unclear. Our present study performed on N-nitroso compounds (NOC) induced gastric epithelial cell transformation revealed a positive correlation of active STAT3 signaling with increased histone H3 phosphorylation. Further analysis showed that mitogen- and-stress activated protein kinase (MSK1) was upregulated by NOC treatment, thereby promoting H3 Ser 10 phosphorylation (H3S10P). Intriguingly, putative STAT3 binding sites were identified in the MSK1 promoter, and we finally confirmed that MSK1 is a novel target gene of STAT3. It has been reported that STAT3 is a direct substrate for MSK1. Therefore, we analyzed the status of STAT3 activation after MSK1 overexpression and knockdown, and a positive feedback loop was found between them. With specific siRNA or inhibitors, we further demonstrated the aberrant activation of STAT3/MSK1/H3S10P axis in MNU-induced gastric cancer (GC) model in mice, human gastric cancer cells, and GC patients. ChIP-seq analysis was performed to determine the H3S10 phosphorylation distribution pattern in NOC-transformed gastric epithelial cells, and some candidate regulated genes were successfully identified. Together, the results of these studies shed light onto a critical role of STAT3 signaling in epigenetic modification network, mediated at least in part by MSK1. Our results suggest that STAT3/MSK1/H3S10P pathway and downstream key effectors represent interesting therapeutic targets in gastric carcinogenesis.
Citation Format: Hongyan Qi, Zhiyi Yang, Shuilian Zhang, Xinxin Ke, Chujun Dai, Jimin Shao, Jing Shen. STAT3 signaling activates MSK1-mediated histone H3 phosphorylation in N-nitrosocompounds induced carcinogenesis [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 5051.
Abstract 5087: Human melanoma exosomes induce metabolic reprogramming in human adult dermal fibroblasts
Authors: Shu Shin La , Allen Cheryl L. , Yang Yunchen , Maguire Orla , Minderman Hans , Sen Arindam , Ciesielski Michael J. , Collins Katherine A. , Bush Peter J. , Morgan Martin , Wu Yun , Bankert Richard B. , Ernstoff Marc S. 
Published: August 2018

Abstract
The “seed and soil” hypothesis of cancer metastasis has led us to examine the role of tumor-derived exosomes on reprogramming stromal cells composing the tumor microenvironment. We used human adult dermal fibroblasts (HADF) in vitro as a model of the premetastatic niche. Specifically, we determined the role of human melanoma-derived exosomes (HMEX) on governing metabolic reprogramming of healthy HADF. HMEX from six melanoma cell lines (3 BRAF V600E mutant cell lines (526-mel, 888-mel and Hs 294T) and 3 BRAF wild-type cell lines (1300-mel, 2183-Her4 and HMCB)) were purified by size-exclusion chromatography. Using the fluorescent tag CellVue (Maroon) we demonstrated via ImageStream that HMEXs are rapidly taken up by HADF. Following 18 hours of exposure to HMEX, HADF increased aerobic glycolysis and reduced oxidative phosphorylation (OXPHOS) in vitro, as measured by Agilent Seahorse XFe96. We have also developed an immuno-biochip that captures exosomes via anti-CD63 antibodies and simultaneously detects exosomal microRNAs by cationic lipoplex nanoparticles (tCLN) containing molecular beacons. With this immuno-biochip, we demonstrated the presence of microRNAs miR-155 and miR-210 in HMEX, both of which work in concert to promote glycolysis and inhibit OXPHOS. The result has been consistent across all HMEXs from the six different melanoma cell lines. Our findings reveal a correlation between metabolic function and the presence of metabolically active microRNAs in HMEX that control aerobic glycolysis and OXPHOS of normal fibroblasts. Melanoma exosomes are potentially key players in promoting tumor progression by modulating normal stromal cell metabolism and creating an environment that is conducive to metastasis.
Oxygen Consumption Rate (OCR) pmol/minHADF onlyHADF + HMEX 17.5 μgHADF + HMEX 25 μgHADF + HMEX 50μgHADF + HMEX100μgBasal OCR52.6753.5850.9638.2031.56
Citation Format: Shin La Shu, Cheryl L. Allen, Yunchen Yang, Orla Maguire, Hans Minderman, Arindam Sen, Michael J. Ciesielski, Katherine A. Collins, Peter J. Bush, Martin Morgan, Yun Wu, Richard B. Bankert, Marc S. Ernstoff. Human melanoma exosomes induce metabolic reprogramming in human adult dermal fibroblasts [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 5087.
Abstract 5091: Maintaining long-term stromal depletion therapy for pancreatic cancer
Authors: Grimaldo Sam R. , Khatibeghdami Mahsa 
Published: August 2018

Abstract
A hallmark feature of pancreatic cancer is a dense fibrotic stroma that surrounds the tumor and sequesters blood vessel growth. The lack of blood vessels results in poor perfusion, causing most therapies to fail. Antistromal therapy via targeting the sonic hedgehog (SHH) pathway is a controversial approach to improving drug distribution for pancreatic cancer. While this approach has been shown to be initially effective, over time stroma depletion results in the return of an aggressive cancer. Long-term stromal depletion creates a microenvironment that permits angiogenesis and fuels the return of an aggressive cancer. It is unknown if inhibiting angiogenesis will improve the long-term success of antistromal therapy. We are pursuing two therapeutic strategies that couple an antiangiogenic component with SHH therapy. These therapeutic strategies will be tested in one of the two novel inducible models we have developed, including the standard iKPC model and an SHH-deleted model iKPC-SHH. Preliminary survival analysis shows overall survival of 8 months and 5 months for the iKPC and iKPC-SHH, respectively. Furthermore, increased CD31 blood vessel staining is seen in the iKPC-SHH model, suggesting increased angiogenesis. Using the standard iKPC we will pursue a co-treatment approach with gemcitabine and the SHH inhibitor, itraconazole, to evaluate the effect on median survival. Itraconazole was chosen from a screen of ten SHH inhibitors and found to have a highest efficacy on vascular endothelial cell (IC50 0.02υM). Thereby we expect this molecule to target both the SHH pathway and blood vessels. The second approach we are pursuing is to determine if the antiangiogenic drug, sunitinib, improves median survival in the iKPC-SHH. The iKPC-SHH serves as a surrogate of antistromal therapy and allows for a focused investigation with antiangiogenic compounds. Sunitinib was chosen from the class of antiangiogenic pharmacologics for its direct efficacy on primary pancreatic tumor cells (IC50 2.4υM); thereby it is expected to target blood vessels and tumor cells in vivo. While both treatments approaches are ongoing. current data show that itraconazole co-treatments are living over 7.5 months in the (noninducible) KPC model. Previous reports with an SHH inhibitor in the KPC model showed a survival at approximately 3-4 months. Thereby our initial data show promise that inhibiting angiogenesis can improve the long-term efficacy of antistromal therapy.
Citation Format: Sam R. Grimaldo, Mahsa Khatibeghdami. Maintaining long-term stromal depletion therapy for pancreatic cancer [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 5091.
Abstract 5101: Characterization of a mouse model using the Sleeping Beauty transposon method to study diffuse intrinsic pontine glioma (DIPG)
Authors: Ravindran Ramya , Mendez Flor M. , Nunez Felipe J. , Koschmann Carl , Dzaman Marta , Pawar Sheeba , Lowenstein Pedro R. , Castro Maria G. 
Published: August 2018

Abstract
Tumors in the brain-stem are difficult to diagnose and treat primarily owing to the location. Diffuse intrinsic pontine glioma (DIPG) is a fatal paediatric brain-stem tumor located in the ventral pons with 100% fatality. These tumors are often treated on the assumption that DIPGs are molecularly similar to adult high grade gliomas; however, they are molecularly distinct. The ACVR1G328V and the H3.1K27M mutations have been seen to recur in DIPGs and we hypothesis that these mutations play an important role in the disease progression. A mutation in the ACVR1 leads to kinase activation and induces downstream signal transduction by phosphorylation of Smads (1/5). H3.1K27M mutations cause genome wide H3K27me3 hypomethylation. We genetically engineered mouse DIPG models using the Sleeping Beauty Transposon (SBT) method to introduce plasmids containing NRASV12/p53-shRNA/ACVR1G328V or NRASV12/p53-shRNA/H3.1K27M into the 4th ventricle of 1-day old pups adjacent to the brain-stem. This generates DIPGs with specific genetic lesions. NRASV12 is a constitutively active oncogene belonging to the RAS family and p53-shRNA is a short hairpin for TP53 tumor suppressor gene. A control tumor model was engineered using plasmids encoding NRASV12 and p53-shRNA. Tumor growth is monitored periodically over time until animals become symptomatic due to tumor burden. At this time point, animals are euthanized and the tumors extracted. We characterized the model for upregulation of phospho-smad 1/5 and markers of neural precursor cells (nestin, Sox2, olig2, GFAP, PDGFRα). In conclusion, we generated a genetically engineered mouse model of DIPG which represents a novel platform to study the molecular pathways underlying disease pathogenesis. An understanding of the functions of mutations that lead up to the disease can help to develop novel therapies for DIPG.
Citation Format: Ramya Ravindran, Flor M. Mendez, Felipe J. Nunez, Carl Koschmann, Marta Dzaman, Sheeba Pawar, Pedro R. Lowenstein, Maria G. Castro. Characterization of a mouse model using the Sleeping Beauty transposon method to study diffuse intrinsic pontine glioma (DIPG) [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 5101.
Abstract 5110: Runx knockout in breast luminal stem/progenitor cells induced precancerous lesion via robust expression of ERα
Authors: Matsuo Junichi , Mon Naing Naing , Yamamura Akihiro , Heng Dede L. , Chuang Linda SH , Osato Motomi , Ito Yoshiaki 
Published: August 2018

Abstract
In breast cancer, 83% of patients were diagnosed as hormone receptor positive, luminal-type, breast cancer (Anderson et al., 2014). Although primary luminal-type breast cancer can be controlled by endocrine therapy, more than 20% of patients have recurrence in 20 years (Pan et al., 2017). Understanding of luminal-type breast cancer would provide benefits to a large number of patients. However, cell of origin and genes responsible for luminal-type breast cancer have not been fully understood. Luminal epithelial cells are considered as origin of breast cancer (Anderson et al., 2014), although not fully proven yet. In addition, extensive genomic analysis of breast cancer patients in TCGA study showed that RUNX genes were downregulated in luminal-type breast cancer: RUNX1 mutation was found in multiple patients, and RUNX3 gene was highly methylated. We previously reported that 270 bp Runx1 enhancer element (eR1) marks hematopoietic stem cell and stomach stem cell (Ng et al., 2010; Matsuo et al., 2017). We also found that this eR1 marks a subset of luminal epithelial cells in mouse mammary gland. Lineage-tracing experiment showed that the eR1+ cells mainly differentiated into luminal cells, but not to basal cells in vivo. These eR1+ cells also contribute to differentiation of alveolar cells in pregnant mice. Interestingly, in vitro lineage tracing by using organoid culture showed that eR1+ cells differentiated into both liminal and basal cells. Runx1 and Runx3 knockout in luminal stem cells showed increase of cell growth, and histology was similar to precancerous lesion such as hyperplasia and ductal carcinoma in situ (DCIS). These lesions showed robust expression of ERα compared with control mice. These results suggested that depletion of Runx in luminal stem cells induces precancerous lesion via robust expression of ERα.
References:
Anderson WF, Rosenberg PS, Prat A, et al. How many etiological subtypes of breast cancer: Two, three, four, or more? J Natl Cancer Inst 2014;106.
Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med 2017:1836-46.
Ng CE, Yokomizo T, Yamashita N, et al. A Runx1 intronic enhancer marks hemogenic endothelial cells and hematopoietic stem cells. Stem Cells 2010:1869-81.
Matsuo J, Kimura S, Yamamura A, et al. Identification of stem cells in the epithelium of the stomach corpus and antrum of mice. Gastroenterology 2017:218-31.
Citation Format: Junichi Matsuo, Naing Naing Mon, Akihiro Yamamura, Dede L. Heng, Linda SH Chuang, Motomi Osato, Yoshiaki Ito. Runx knockout in breast luminal stem/progenitor cells induced precancerous lesion via robust expression of ERα [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 5110.
Abstract 5120: Adipocyte-derived lipids mediate melanoma progression via FATP proteins
Authors: Zhang Maomao 
Published: August 2018

Abstract
During melanoma progression, tumor cells come into direct contact with subcutaneous tissues and these advanced lesions portend a poor prognosis. Despite the fact that subcutaneous tissues are largely composed of adipocytes, little is known about the mechanisms by which adipocytes influence melanoma. Using both in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. This is accompanied by direct transfer of fatty acids from adipocytes to melanoma cells, which increases tumor cell metabolism and invasion programs. These adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six related FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. These data demonstrate that adipocytes in the tumor microenvironment can drive melanoma progression through FATP lipid transporters, and represents a new target aimed at interrupting adipocyte-melanoma crosstalk.
Citation Format: Maomao Zhang. Adipocyte-derived lipids mediate melanoma progression via FATP proteins [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 5120.
Abstract 5134: Desacetylvinblastine monohydrazide disrupts tumor vessels by promoting VE-cadherin internalization
Authors: Chen Minfeng , Lei Xueping , Ye Wencai , Zhang Dongmei 
Published: August 2018

Abstract
Vinca alkaloids, the well-known tubulin-binding agents, are widely used for the clinical treatment of malignant tumors. However, little attention has been paid to their vascular disrupting effects, and the underlying mechanisms remain largely unknown. This study aims to investigate the vascular disrupting effect and the underlying mechanisms of vinca alkaloids.
Methods: The capillary disruption assay and aortic ring assay were performed to evaluate the in vitro vascular disrupting effect of desacetylvinblastine monohydrazide (DAVLBH), a derivate of vinblastine, and the in vivo vascular disrupting effect was assessed on HepG2 xenograft model using magnetic resonance imaging, hematoxylin and eosin staining and immunohistochemistry. Tubulin polymerization, endothelial cell monolayer permeability, western blotting and immunofluorescence assays were performed to explore the underlying mechanisms of DAVLBH-mediated tumor vascular disruption.
Results: DAVLBH has potent vascular disrupting activity both in vitro and in vivo. DAVLBH disrupts tumor vessels in a different manner than classical tubulin-targeting VDAs; it inhibits microtubule polymerization, promotes the internalization of vascular endothelial cadherin (VE-cadherin) and inhibits the recycling of internalized VE-cadherin to the cell membrane, thus increasing endothelial cell permeability and ultimately resulting in vascular disruption. DAVLBH-mediated promotion of VE-cadherin internalization and inhibition of internalized VE-cadherin recycling back to the cell membrane are partly dependent on inhibition of microtubule polymerization, and Src activation is involved in DAVLBH-induced VE-cadherin internalization.
Conclusions: This study sheds light on the tumor vascular disrupting effect and
underlying mechanisms of vinca alkaloids and provides new insight into the molecular mechanism of tubulin-targeting VDAs.
Key words: Vascular disrupting agents; vinca alkaloids; desacetylvinblastine monohydrazide; tubulin polymerization; VE-cadherin internalization
Citation Format: Minfeng Chen, Xueping Lei, Wencai Ye, Dongmei Zhang. Desacetylvinblastine monohydrazide disrupts tumor vessels by promoting VE-cadherin internalization [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 5134.
Abstract 5151: Enhanced chemotactic response of MDA-MB-231 breast cancer cells towards stable gradients of EGF
Authors: Baumann Nina , Kuttenberger Verena , Huemmer Christine , Schwarz Jan , Horn Elias Horn , Zantl Roman 
Published: August 2018

Abstract
Chemotactic cell migration is a basic mechanism underlying cancer cell invasion and hence metastasis. In this regard, growth factors such as epidermal growth factor (EGF) have been identified as guidance cues. Using ibidi's µ-Slide Chemotaxis we confirm the growth factor EGF as potent guidance cue for directional MDA-MB-231 migration in a physiological 3D environment. Moreover, we find enhanced sensitivity towards gradients of EGF in serum free media supplemented with defined protein composition (UltraCULTURETM). Combining defined, physiological migration conditions and enhanced sensitivity allowed us to quantify EGF dependent MDA-MB-231 chemotaxis in a detailed manor. MDA-MB-231 cells showed increased directional and kinetic response towards temporal and stable spatial gradients of EGF. While EGF guided directional migration was highly concentration dependent with a concentration optimum of 10 ng/mL, we found the chemokinetic effect induced by the presence of EGF being concentration independent. Those results suggest differential response of the migration and signal interpretation machinery of MDA-MB-231 cells. Both, blocking the ligand binding domain of the EGF-Receptor (EGFR) by a blocking antibody and inhibition of the kinase domain of EGFR by a small molecule inhibitor (AG1478) led to a reduction in EGF induced directional sensing and migration velocity. Additionally, low, non-effective single doses of antibody and small molecule inhibitor showed synergistically effective inhibition if combined. Those results support EGF being a potent guidance cue for MDA-MB-231 cell migration and help to understand the mechanisms behind chemotactic migration driven cancer metastasis.
Citation Format: Nina Baumann, Verena Kuttenberger, Christine Huemmer, Jan Schwarz, Elias Horn Horn, Roman Zantl. Enhanced chemotactic response of MDA-MB-231 breast cancer cells towards stable gradients of EGF [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 5151.