bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2699: Organ-specific signatures of melanoma metastasis.
Authors: Sundstrøm Terje , Prestegarden Lars , Tepper Clifford , Ingham Elizabeth , Even Lisa , Johnson Sarah , Skaftnesmo Kai Ove , Lund-Johansen Morten , Bjerkvig Rolf , Ferrara Katherine , Thorsen Frits 
Published: August 2014

Abstract
We have previously reported on a reproducible and predictive animal model that can be used to elucidate the enigmatic biology of melanoma metastasis, a key prerequisite for therapeutic advances. Here, we have used this model to investigate the molecular drivers responsible for metastasis formation in different organs, with a special emphasis on brain-specific features. A human melanoma brain metastasis cell line (H1) was developed in our laboratory, transduced with the genes for green fluorescent protein and luciferase, and injected into the left cardiac ventricle of seven immunodeficient mice. Whole-body bioluminescence imaging (BLI) and brain magnetic resonance imaging was performed weekly to follow the development of metastases. The animals invariably developed both intracranial and extracranial tumors. At about seven weeks, the animals were euthanized and organ involvement was examined in detail by ex vivo BLI. The brain, femurs, adrenals, and ovaries from five random animals were enzymatically dissociated using organ-tailored protocols. Sample yield was validated by fluorescence microscopy prior to fluorescence-activated cell sorting of tumor cells. Three tumor cell samples from the brain, femurs, adrenals, and ovaries of different mice were then analyzed using next-generation RNA-sequencing (NGS) technology. We also performed baseline NGS on the H1 cell line before injection. Taken together, bioinformatics analysis revealed unique molecular signatures of organ-specific metastasis, validating some previously reported metastasis drivers and introducing other genomic features critical to the detrimental momentum of metastatic melanoma.
Citation Format: Terje Sundstrøm, Lars Prestegarden, Clifford Tepper, Elizabeth Ingham, Lisa Even, Sarah Johnson, Kai Ove Skaftnesmo, Morten Lund-Johansen, Rolf Bjerkvig, Katherine Ferrara, Frits Thorsen. Organ-specific signatures of melanoma metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2699. doi:10.1158/1538-7445.AM2013-2699
Abstract 2713: The Pten and p53 tumor suppressors cooperate to constrain the PI3K/mTOR pathway activation.
Authors: Liu Pixu , Cheng Hailing , Symonds Lynn , Xu Erbo , Maira Sauveur-Michel , di Tomaso Emmanuelle , Roberts Thomas , Zhao Jean 
Published: August 2014

Abstract
Loss of Pten expression and mutational inactivation of p53 are frequent molecular events in liver cancer associated with advanced disease stage and poor prognosis. The tumor suppressor PTEN is a phosphoinositide phosphatase that antagonizes the class IA PI3K-engaged oncogenic signaling by dephosphorylating PtdIns(3,4,5)P(3); however, the specific roles of class IA PI3K isoforms, p110a and p110b, have not been assessed in genetically engineered mouse models of liver cancer with Pten inactivation. Furthermore, effective treatment strategies for Pten and p53 deficient liver malignancy remain to be defined. In this study, we showed that combined deletion of Pten and p53 in liver led to rapid development of hepatocellular carcinoma and cholangiocellular carcinoma, the two most common types of liver cancer, with complete penetrance. While a single ablation of p110a or p110b markedly reduced the tumor burden, inactivation of both p110a and p110b completely blocked the liver tumorigenesis. Although liver tumors driven by inactivation of Pten and p53 showed a good response to GDC-0941, a pan-PI3K inhibitor, the combined treatment with both GDC-0941 and Rad001, an mTOR inhibitor or single-agent BEZ235, a dual pan-PI3K and mTOR inhibitor, led to marked tumor regression. These studies suggest that Pten and p53 cooperate to constrain the PI3K/mTOR pathway activation and inhibitors targeting both PI3K and mTOR may effectively treat Pten and p53 deficient liver cancers.
Citation Format: Pixu Liu, Hailing Cheng, Lynn Symonds, Erbo Xu, Sauveur-Michel Maira, Emmanuelle di Tomaso, Thomas Roberts, Jean Zhao. The Pten and p53 tumor suppressors cooperate to constrain the PI3K/mTOR pathway activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2013-2713
Abstract 2718: Spheroid culture of colorectal cancer cells from patient tumor tissue preserves important cellular characteristics of the parental tumor.
Authors: Jeppesen Maria , Hagel Grith , Glenthoj Anders , Thastrup Ole , Jorgensen Lars Nannestad , Thastrup Jacob 
Published: August 2014

Abstract
At the time of diagnosis more than 65% of patients with colorectal cancer have advanced disease and require chemotherapeutic treatment. However, colorectal tumors demonstrate pronounced heterogeneity, leading to significant individual variation in sensitivity to standard chemotherapeutic drugs. Tools for assessing chemosensitivity and tailoring therapeutic regimens to the individual patient are therefore urgently needed. A promising approach is to isolate viable cancer cells from patient tissue and to test the chemosensitivity of the individual tumor in vitro.
The aim of the current study was to establish primary colorectal cancer cell cultures from patient tissue and investigate if the cultured cells retain important characteristics of the original tumor. Small cell clusters were isolated from colorectal tumor tissue and allowed to form cell spheroids in suspension culture. The cell type composition of patient spheroids was characterized by immunostaining with cell type specific antibodies. Spheroid size was monitored over time and growth curves established for each patient. The distribution of proliferating and apoptotic cells in the spheroids was assessed by staining for specific markers. The 3D culture system was verified as a tumor model by comparing the results obtained for the spheroids to paraffin-embedded sections of the original tumors.
Successful spheroid culture was obtained from more than 80% of tissue samples. Immunostaining confirmed that the primary cultures were composed of colorectal cancer cells, without significant contaminations by other cell types. Growth could be observed as an increase in spheroid size. The dominating cell populations of the original tumor could generally be identified in the derived spheroids as well. In summary, spheroid cultures of colorectal cancer cells can be established from tumor tissue of individual patients with a high success rate and the formed spheroids retain important cellular characteristics of the original tumor. Culture of colorectal cancer cells as spheroids represents a promising method for establishing primary cultures for chemotherapeutic screening of the individual patient.
Citation Format: Maria Jeppesen, Grith Hagel, Anders Glenthoj, Ole Thastrup, Lars Nannestad Jorgensen, Jacob Thastrup. Spheroid culture of colorectal cancer cells from patient tumor tissue preserves important cellular characteristics of the parental tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2718. doi:10.1158/1538-7445.AM2013-2718
Abstract 2722: Characteristics of pancreatic cancer spheroids as a model for anticancer efficacy test.
Authors: Yeon Sang-Eun , Lee Sang-Hoon , Kuh Hyo-Jeong 
Published: August 2014

Abstract
Compared to the conventional monolayers or suspension cultures, 3D culture models have drawn attention as a vivo-mimic model which can produce clinically relevant data. Among the several types of 3D culture models, multicellular spheroid (MCS) is a appropriate model for study of penetration and efficacy of anticancer agents. Purpose of this study was to establish MCS of human pancreatic cancer cell (Panc-1) and evaluate its usefulness as anticancer efficacy test. Panc-1 MCS was produced successfully by using poly-dimethylsiloxane(PDMS) microwell instead of agarose-coated 96-well system. MCS with average diameter of 375 μm was prepared in 700 μm microwells after 4 days of culture. Spherical morphology with rather rough surface and junctional structures in outer cell layers were observed with no notable necrotic area. Extracellular matrix proteins such as collagen I, fibronectin, and laminin were detected in the interstitial space of MCS. Stem cell population with CD44+/CD24+/ESA+ expression increased from 0.1% to 2.1% when cultured as MCS. miRNA expression profiling showed a difference between monolayers and MCS, i.e., 36 and 85 genes were up- and down-regulated in MCS, respectively. Imaging of drug penetration and viability indicators including MitoSOX, Edu incorporation, and Ki-67 expression were optimized for microwell format. Colorimetric assays of MTS and APH were performed after transferring MCS to 96-well plates. Overall, we demonstrated that PDMS microwell is an appropriate platform for preparation of MCS of Panc-1 cells and MCS showed different biological features from monolayers, suggesting that Panc-1 MCS prepared using PDMS microwell may be a useful 3D model for anticancer efficacy test.
Citation Format: Sang-Eun Yeon, Sang-Hoon Lee, Hyo-Jeong Kuh. Characteristics of pancreatic cancer spheroids as a model for anticancer efficacy test. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2722. doi:10.1158/1538-7445.AM2013-2722
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2737: Spontaneous genomic alterations identified in a chimeric model of colorectal cancer guide effective combinatorial therapy.
Authors: Zhou Yinghui , Rideout William M. , Bressel Angela , Yalavarthi Sireesha , Zi Tong , Monti Anthony , Bottega Steve , Feng Bin , Chiu M. Isabel , Bosenberg Marcus , Heyer Joerg 
Published: August 2014

Abstract
Colon cancer is the second most common cause of cancer mortality in the western world. We generated a mouse model of colon cancer in which a conditional mutation of p53 is combined with inducible delta131-beta-Catenin over-expression in the intestinal epithelium. After 4-12 months of beta-Catenin induction, small adenomas and large solitary nodules of invasive adenocarcinomas developed in either the upper or lower intestinal tract, while the remainder of the intestine appeared normal. Molecular analysis revealed that EGFR and MET were expressed in advanced adenocarcinomas but not early stage adenomas. Although propagating mouse colon tumors has been very challenging, we nevertheless successfully established one tumor line through direct in vivo propagation in the kidney capsule. This tumor line, CB42, grew aggressively and metastasized to ancillary lymph nodes as well as the lung in a subcutaneous metastasis assay and grew in the liver when seeded there by intra splenic injection. Treatment with a MET inhibitor Crizotinib, had no effect on either primary tumor growth, or metastasis. By comparing the genome of CB42 with other colon tumors that did not propagate, we discovered an amplicon on chromosome five containing genes that correlated with propagation and metastasis. In addition, whole genome sequencing revealed that CB42 harbored a mutation in KRAS. Results from combination therapies against key genetic alterations will be presented.
Citation Format: Yinghui Zhou, William M. Rideout, Angela Bressel, Sireesha Yalavarthi, Tong Zi, Anthony Monti, Steve Bottega, Bin Feng, M. Isabel Chiu, Marcus Bosenberg, Joerg Heyer. Spontaneous genomic alterations identified in a chimeric model of colorectal cancer guide effective combinatorial therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2737. doi:10.1158/1538-7445.AM2013-2737
Abstract 2741: NF-κB activation by IL-1α and p62 feedforward loops is required for Kras-induced pancreatic ductal adenocarcinoma.
Authors: Ling Jianhua , Kang Ya'an , Chiao Paul 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a less than six month mean survival period and less than five percent of an overall five-year survival rate. Despite developments in the management of pancreatic cancer, the survival rate has remained unchanged in the past 50 years. Thus, a better understanding of the mechanism of pancreatic cancer inception and development is the key to identifying prevention strategies and therapeutic targets for increasing patient survival rates, which is one of the greatest challenges in pancreatic cancer research.
The mutational activation of Kras is an early event in PDAC development and has been detected in 90% of PDAC and 50% of pancreatic intraepithelial neoplasia (PanIN). The genetic mutation of oncogenic Kras in the pancreas induces chronic pancreatitis and pancreatic cancer. However, the key signaling pathway of the downstream Kras remains unidentified.
Here, we report that pancreas-specific targeted IKK2/β inactivation inhibited NF-κB activation and PDAC development in KrasG12D and KrasG12D; Ink4a/ArfF/F mice, demonstrating a mechanistic link between IKK2/β/NF-kB signaling pathway and KrasG12D signaling pathways in PDAC inception. Our findings reveal that KrasG12D-activated AP-1 induces IL-1α, which, in turn, activates NF-κB and its target genes IL-1α and p62, to initiate IL-1α/p62 feedforward loops for inducing and sustaining NF-κB activity. Furthermore, IL-1α overexpression correlates with Kras mutation, NF-κB activity, and poor survival in PDAC patients. Knock-down of IL-1α in mouse PDAC cell lines and lung adenocarcinoma cell lines significantly reduces tumorigenesis in orthotopic xenograft mouse and subcutaneous xenograft mouse models. Therefore, our findings demonstrate the new mechanism by which IKK2/β/NF-κB is activated by KrasG12D through dual feedforward loops of IL-1α/p62 to promote development of PDAC. This suggests that the interruption of the dual feedforward loops of IL-1α/p62 could be the therapeutic targets for inhibiting oncogenic Kras signaling in PDAC.
Citation Format: Jianhua Ling, Ya'an Kang, Paul Chiao. NF-κB activation by IL-1α and p62 feedforward loops is required for Kras-induced pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2013-2741
Abstract 2742: Activation of Wnt/β-catenin signaling accelerates progression of Kras-induced pancreatic cancer.
Authors: Sano Makoto , Driscoll David R. , DeJesus-Monge Wilfredo E. , Klimstra David S. , Lewis Brian C. 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of the Wnt signaling pathway is also commonly observed in PDAC. To ascertain the impact of postnatal activation of the Wnt signaling pathways in PDAC development, we combined the elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-cateninS37A and Wnt1 stimulated the progression of premalignant PanIN and PDAC development. Moreover, mice injected with RCAS-β-cateninS37A and Wnt1 had reduced survival relative to RCAS-GFP controls (log-rank test; p &lt; 0.05). Meanwhile, active β-catenin or its DNA-binding partner TCF4 enhanced PDAC cell proliferation, soft-agar colony formation, as well as migration and invasion activity. In contrast, these phenotypes were significantly blocked by the introduction of Icat, an inhibitor of the β-catenin/TCF4 interaction. Interestingly, Id2 (inhibitor of differentiation/DNA binding2) was significantly up-regulated by induction of β-catenin and TCF4, whereas Id2 expression was inhibited by Icat. Furthermore, nuclear β-catenin and Id2 were mainly observed in poorly differentiated PDACs and sarcomatoid tumors. Together, these data suggest that the Wnt/β-catenin signaling pathway stimulates pancreatic tumor development and progression through the activation of Id2.
Citation Format: Makoto Sano, David R. Driscoll, Wilfredo E. DeJesus-Monge, David S. Klimstra, Brian C. Lewis. Activation of Wnt/β-catenin signaling accelerates progression of Kras-induced pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2742. doi:10.1158/1538-7445.AM2013-2742
Abstract 275: Development of RNAi-dendrimer-based Twist1 inhibitors to reduce metastasis and recurrence in ovarian cancer.
Authors: Roberts Cai , Finlay James , Lowe Gina , Dellinger Thanh H. , Han Ernest , Glackin Carlotta 
Published: August 2014

Abstract
Background/Objective: Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer, with the vast majority of patients eventually developing a recurrence. One promising novel therapeutic target is Twist1, a basic helix-loop-helix transcription factor that acts as a master regulator of epithelial to mesenchymal transition (EMT), an important step in metastasis, of which loss of E-cadherin is the hallmark. Furthermore, Twist1 is a key component in the differentiation of EOC stem cells into metastatic cancer cells.
Methods: We investigated the effectiveness of three siTwist-candidates and two types of Poly (amidoamine) (PAMAM) dendrimers on intracellular delivery of siRNA to ovarian cancer cell lines. The EOC cell lines TOV112D, TARA R182 (immortalized primary EOC cells) and A2780R (cisplatin-resistant derivatives of the A2780 EOC cell line) were used. Two types of PAMAM dendrimers, Generation 5 (G5) and a new G3 dendrimer (YTZ3-15) were examined, which differ based on the numbers of surface amines. We complexed multiple Twist1-specific siRNA constructs to PAMAM dendrimers to protect fragile RNA and facilitate delivery. We loaded G5 and YTZ3-15 dendrimers with Cy3-labeled siTwist-506 and transfected TOV112D cells with these complexes. Quantitative real-time PCR (QPCR) and Western blotting were used to evaluate Twist1 knockdown in four EOC cell lines following transfection with siTwist.
Results: Bright field and fluorescent microscopy analysis showed that ∼95-98% of TOV112D cells contained Cy3 label, indicating that both the G5 and YTZ3-15 dendrimers can penetrate the cell membranes of EOC cells. Cy3-labeled siTwist-506 led to a 50% reduction in Twist1 mRNA in these cells. Further analysis revealed that novel siRNA sequences siTwist-419 and 494 significantly reduced Twist1 protein expression compared to siTw506 and non-transfected controls, and real-time RT-PCR analysis revealed a 80% reduction in Twist1 mRNA in both TARA R182 and A2780R EOC cells. This suggests that siTwist-419 and 494 can lead to optimal Twist1 silencing.
Conclusions: Our data support the feasibility of using siTwist-dendriplex approaches to knock down Twist1 expression in EOC cells, by circumventing a major obstacle to the targeting of transcription factors with dendrimer technology. Further studies are needed to prove whether the prevention of Twist1 production will reduce EOC metastases, and prevent recurrences by arresting EOC stem cells in an undifferentiated state.
Citation Format: Cai Roberts, James Finlay, Gina Lowe, Thanh H. Dellinger, Ernest Han, Carlotta Glackin. Development of RNAi-dendrimer-based Twist1 inhibitors to reduce metastasis and recurrence in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 275. doi:10.1158/1538-7445.AM2013-275
Abstract 282: Vimentin serves as a signaling scaffold at focal adhesion sites to regulate lung cancer cell adhesion.
Authors: Havel Lauren , Marcus Adam I. 
Published: August 2014

Abstract
Vimentin is a dynamic type III intermediate filament that is overexpressed in various cancers including non-small cell lung cancer (NSCLC). It is a classic biomarker for highly invasive tumors and is associated with increased likelihood of metastasis and poor survival. Vimentin filaments are dynamic and localize to focal adhesions, where they assemble and disassemble to promote cell migration. Our data show that vimentin depletion reduces cell adhesion and phosphorylated focal adhesion kinase (pFAK); therefore, we hypothesize that vimentin acts through FAK to regulate cell adhesion and metastasis. We show that vimentin filaments enter pFAK- and pSrc-positive focal adhesion sites, and upon vimentin depletion, pFAK, pSrc and total FAK levels decrease. To explore the mechanism behind this observation, we performed a phospho-proteomic screen for proteins whose phosphorylation is altered upon vimentin loss. One of the identified proteins was a guanine nucleotide exchange factor (GEF) that regulates rac1. We show that vimentin loss leads to GEF mis-localization and downstream rac1 inactivation. Furthermore, inactivation of the GEF itself resulted in aberrant cellular adhesion and loss of pFAK. Based upon this data, we propose that vimentin serves as a signaling scaffold to regulate FAK via a rac1-GEF interaction. This work provides insight into the mechanism by which vimentin affects cell adhesion and potentially NSCLC metastasis.
Citation Format: Lauren Havel, Adam I. Marcus. Vimentin serves as a signaling scaffold at focal adhesion sites to regulate lung cancer cell adhesion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 282. doi:10.1158/1538-7445.AM2013-282