bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 481: The role of jaspamide in the actin cytoskeleton of melanoma cells: The relation between migration and invasion
Authors: Menezes Michelle S. , Martens Adam , Niero Evandro Luis O. , Siviero Fabio , Machado-Santelli Glaucia M. 
Published: August 2012

Abstract
Metastasis is the leading cause of melanoma mortality. The metastatic cascade represents a multi-step process which includes several cellular and molecular processes including cell migration and invasion. Tumor cells can migrate either collectively, in a mesenchymal or in an amoeboid type of movement. The role of microfilaments is essential in mesenchymal migration, where it acts in the formation of membrane protrusions, and amoeboid migration, where they play a key role in cell contraction. In this context, the present work aimed to analyze the effects of the marine sponge-derived drug jaspamide, which has well-known properties on cytoskeleton (anti-polymerizing of the actin microfilaments). After the determination of the IC50 concentrations for the HT144 (derived from human melanoma) and NGM (from human benign nevus) cell lines, the effects of the treatment with jaspamide were studied through wound assays, transwell assays, Boyden's chamber assays, fluorescent cytochemistry, immunofluorescence and Western blotting. The treatments demonstrated the drug acts disorganizing the microfilament cytoskeleton in a dose-dependent way, leading the accumulation of F-actin in the perinuclear region. The wound assays indicated that drug treatment impaired the migration ability of both cell lines. However assays in Boyden's chambers showed increasing in cell migration in consequence of jaspamide treatment, result that could be explained by switch of the migration strategy from mesenchymal to ameboid. This fact was corroborated by the decreased expression of the IRSp53 protein after jaspamide treatment meanwhile MT1-MMP expression is not affected by the treatment. By treating thecell lines with the compounds Y-27632 or NSC23766 in addition to jaspamide, it is possible to conclude that NGM cells use mainly the RAc signaling pathway to control cellular migration process. In contrast, the melanoma cell line HT144 however could use either Rac or Rho pathway to migrate. Key words: Melanoma. Jaspamide. Migration. Invasion. Metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 481. doi:1538-7445.AM2012-481
Abstract 4837: Tumor microenvironment contributes to RAF-inhibitor resistance through HGF secretion
Authors: Straussman Ravid , Morikawa Teppei , Shee Kevin , Barzily-Ronki Michal , Du Jinyan , Davis Ashli , Gould Joshua , Flaherty Keith T. , Ogino Shuji , Wargo Jennifer A. , Golub Todd R. 
Published: August 2012

Abstract
Drug resistance remains a vexing problem in the treatment of cancer patients. While many studies have focused on cell autonomous mechanisms of drug resistance, we hypothesized that the tumor microenvironment may confer innate resistance to therapy. We employed a novel co-culture assay to systematically assay the ability of 23 stromal cell types to influence the sensitivity of 45 cancer cell lines to 35 anti-cancer drugs testing more than 15,000 cancer-stroma-drug combinations. We found that stroma-mediated resistance is surprisingly common - particularly to targeted chemotherapies. We decided to further characterize the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibition because most patients exhibit some degree of innate resistance. Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the MAPK and PI3K/AKT pathways, and immediate resistance to RAF inhibition. Immunohistochemistry confirmed tumor stromal HGF expression in 11 out of 15 patients with BRAF-mutant melanoma. Among these patients, only one experienced a complete response, and that patient was negative for stromal HGF, consistent with our prediction of HGF-mediated RAF-inhibitor resistance. In contrast, of 6 evaluable patients with stable disease 4 had particularly high levels of stromal HGF expression. Dual inhibition of RAF and MET in BRAF-mutant melanoma cell lines resulted in reversal of drug resistance, suggesting RAF/MET combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. Interestingly, the activation of MET in these cell lines was cell autonomous, caused, for example, by autocrine secretion of HGF and resulting in complete resistance to RAF inhibitors even in the absence of stromal cells. Treatment with a MET inhibitor re-sensitized these cell lines to RAF inhibitors suggesting the same RAF/MET combination therapy for non-melanoma BRAF mutant cancers as well. More generally, these studies indicate that the systematic dissection of tumor-microenvironment interactions may reveal important mechanisms underlying drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4837. doi:1538-7445.AM2012-4837
Abstract 4838: Upregulation of ERBB3/HER3 by FOXD3, an adaptive response promoting resistance to RAF/MEK-inhibitors
Authors: Abel Ethan V. , Basile Kevin J. , Aplin Andrew E. 
Published: August 2012

Abstract
Targeting the B-RAF/MEK/ERK pathway has shown promise in the treatment of mutant B-RAF melanomas, but resistance to RAF/MEK-inhibitors has been observed. We have previously shown that the stem cell transcription factor FOXD3 is upregulated in mutant B-RAF melanoma cells upon RAF/MEK-inhibition, but the consequences of FOXD3 upregulation are unclear. Using microarrays and ChIP-sequencing, we identified ERBB3/HER3 as a direct target of FOXD3. FOXD3 enhanced ERBB3 expression and responsiveness to its ligand neuregulin-1 (NRG1). Interestingly, PLX4032 or AZD6244-treated cells displayed enhanced NRG1-dependent ERBB3 phosphorylation and downstream AKT activation. These effects were associated with NRG1 enhanced migration and growth of RAF/MEK-inhibitor treated cells in vitro. Phosphorylation of ERBB3 was found to be dependent on ERBB2/HER2, as NRG1/ERBB3-signaling was inhibited by ERBB2-targeting siRNA, the ERBB2-blocking antibody trastuzumab and the ERBB2-inhibitor lapatinib. Additionally, the combination of lapatinib and PLX4032 was more effective than either alone at inhibiting colony formation in the presence or absence of NRG1. Similarly, we found that combining lapatinib with PLX4720 was more effective than either drug alone at reducing tumor burden in melanoma xenografts. These results suggest that upregulation of ERBB3 by FOXD3 serves as an adaptive response to protect melanoma cells from the effects of RAF/MEK-inhibitors and promotes resistance. In summary, targeting the NRG1/ERBB3 pathway in conjunction with RAF/MEK may provide a clinical benefit.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4838. doi:1538-7445.AM2012-4838
Abstract 4850: Sensitization to chemotherapy through interference with FOXO4 - a pivotal node between senescence and apoptosis
Authors: de Keizer Peter L. j. , Campisi Judith 
Published: August 2012

Abstract
Malignant transformation of damaged cells is restricted through activation of potent tumor suppressive mechanisms as apoptosis and cellular senescence. While apoptotic cells are cleared from the organism, senescent cells are withdrawn from the cell cycle, remain present in the organism and accumulate with age. Senescent cells retain the capacity to become tumorigenic upon acquisition of additional mutations. Forcing a shift from the senescence program towards apoptosis may therefore prove clinically useful as treatment for senescence-escaped tumors. Unfortunately, it is still unclear why certain cells undergo apoptosis whereas others enter senescence in response to identical stimuli. We establish the transcription factor FOXO4 as a pivot in this decision process. FOXO4 expression is elevated in DNA-damaged cells, associated with its recruitment to focal sites of DNA damage. Treatment of primary cultures that would otherwise senesce in response to DNA-damaging insults could be pushed towards apoptosis by interference with FOXO4 expression. This formed the basis for a series of experiments addressing the potential role of FOXO4 in tumor survival. Recently, the BRAFV600E-specific drug Vemurafenib has been shown to significantly enhance tumor-free survival rates of malignant melanoma patients carrying this mutation, but in time recurrence tends to occur. Excitingly, we observed that interference with FOXO4 expression in BRAFV600E-driven malignant melanomas sensitized them to Vemurafenib as well as their “classical” chemotherapeutic agent Dacarbazine. Several NRAS-mutated melanoma lines could furthermore be spontaneously induced to apoptose by FOXO4 interference. Finally, these observations are not limited to melanoma and interference with FOXO4 also sensitized mammary carcinoma cells toward 5-fluorouracyl and prostate carcinoma cells towards Mitoxantrone. We are currently exploring the potential of targeted anti-FOXO4 therapy in vivo to see whether FOXO4 could provide a general Achilles’ heel in the survival of malignant carcinomas. This work is supported by post-doctoral fellowship Buit-4649 of the Dutch Cancer Society awarded to PLJDK and NIH grant AG017242 awarded to JC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4850. doi:1538-7445.AM2012-4850
Abstract 4851: Selective small molecule inhibition of anti-apoptotic MCL-1
Authors: Cohen Nicole A. , Stewart Michelle L. , Gavathiotis Evripidis , Tepper Jared L. , Opferman Joseph T. , Walensky Loren D. 
Published: August 2012

Abstract
BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway in health and disease. Anti-apoptotic members such as BCL-2, BCL-XL, and MCL-1 have been implicated in the initiation, progression, and chemoresistance of human cancer. The anti-apoptotic BCL-2/BCL-XL groove that binds and sequesters pro-apoptotic BH3 death helices has been successfully targeted by small molecules and peptides. Such compounds induce tumor cell apoptosis and are being advanced in clinical trials as promising next-generation cancer therapeutics. Notably, selective antagonists such as ABT-737 are highly effective at inducing apoptosis in BCL-2/BCL-XL-dependent cancers, but are rendered inactive by overexpression of MCL-1, a formidable chemoresistance protein that lies outside the molecule's binding spectrum. By screening a library of Stabilized Alpha-Helix of BCL-2 domains (SAHBs), we previously discovered that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor (Stewart et al., Nat Chem Biol, 2010). Here, we deployed this natural peptidic inhibitor of MCL-1 in a competitive binding screen to identify an MCL-1 inhibitor molecule (MIM) that displays exquisite selectivity in in vitro binding and functional assays. NMR analysis documented that MIM engages the canonical BH3-binding pocket of MCL-1. Importantly, MIM selectively triggers caspase 3/7 activation and apoptosis in a cancer cell line that is dependent on induced overexpression of MCL-1, but showed no activity in the isogenic cell line that is driven instead by overexpressed BCL-XL. Conversely, ABT-737 manifested activity in the BCL-XL-overexpressing cancer cells but had no effect on the corresponding MCL-1-dependent cells. Thus, we report the application of MCL-1 SAHB to identify a selective small molecule inhibitor of MCL-1 that exhibits pro-apoptotic activity in the specific context of MCL-1 dependence.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4851. doi:1538-7445.AM2012-4851
Abstract 491: Endoglin suppresses prostate cancer invasion through two distinct type II TGF-β receptors
Authors: Breen Michael J. , Moran Diarmuid M. , Bergan Raymond C. 
Published: August 2012

Abstract
Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer-related death. Death from PCa results from the development of metastatic disease, yet the processes underlying progression from localized to invasive and ultimately metastatic disease remain poorly understood. Our group has previously shown that endoglin, an auxiliary TGF-β superfamily receptor, is lost with PCa progression. Restoration of endoglin expression inhibits PCa cell migration, invasion, and metastasis in pre-clinical models. Endoglin-mediated suppression of PCa invasion (EMSI) is mediated through the type I TGF-β receptor ALK2 and the downstream effector Smad1. Given that TGF-β signaling minimally requires both a type I and a type II TGF-β receptor (RII), we sought to determine the RII(s) involved in EMSI. We now show that silencing of either the type IIA activin receptor (ActRII) or the type II bone morphogenic protein receptor (BMPRII) abrogates endoglin's invasion suppressive effects. Surprisingly, ActRII and BMPR2 have opposite effects on downstream Smad1 signaling: ActRII promotes basal and endoglin-mediated Smad1 transcriptional activity dependent on its kinase domain, while BMPR2 suppresses Smad1 transcriptional activity independent of its kinase domain but dependent on its cytoplasmic tail. Moreover, we show that engagement of distinct BMP-responsive R-Smads (i.e. Smad1, Smad5, & Smad8) does not account for differential signaling and confirm that Smad1 is the main mediator downstream of endoglin. We posit the existence of two parallel pathways that are required for EMSI: an ActRII / ALK2 / Smad1 pathway and a second, as-yet-uncharacterized pathway involving BMPR2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 491. doi:1538-7445.AM2012-491
Abstract 4919: Pathway profiling of head and neck cancer cell lines
Authors: Zuo Zhixiang , Braegelmann Johannes , Keck Michaela , Shen Wanda , Dinali Mohamed El , Vokes Everett E. , Seiwert Tanguy Y. 
Published: August 2012

Abstract
Introduction: Cell lines retain key genetic aberrations of the originating tumors, which frequently correlate with sensitivity to specific inhibitors. We performed genetic and pathway based profiling of 40 head and neck cancer (HNC) cell lines using three publicly available methods for pathway profiling based on expression and copy number data. Methods: 40 HNC cell lines were analyzed for expression using expression arrays (Agilent), and copy number using array comparative hybridization (aCGH) and/or Nanostring methodologies. Integrative genomic analysis was performed to determine pathway activity using pathway analysis techniques previously described by Gatza et al. (BFRM), Pe'er et al (CONEXIC), Vaske et al. (PARADIGM). Results: Frequent pathway activation was identified in &gt;10 well established signalling pathways for HNC including TP53, PI3K-AKT, TP63/SOX2, Cyclin D1, MYC etc, as well as several - for HNC previously unknown - signalling pathways. Cell lines could be associated with expression-based biologic subtypes in HNC tissues suggesting that specific cell lines should be used preferentially for modelling and therapeutic evaluation for HNC subtypes (including HPV(+) cell lines with characteristics of HPV(+) tumors). The three pathway analysis platforms identified a large number of pathways with some overlap in particular between BFRM and CONEXIC, whereas PARADIGM profiled a much wider set of pathways. Both CONEXIC and PARADIGM employed copy number data, whereas BFRM relied solely on expression data. Conclusion: Pathway alterations characteristic of head and neck cancers were identified in virtually all HNC cell lines. Pathway based classification of cell lines was achieved and correlated with pathway activity in HNC tumor tissues. Three pathway-profiling approaches provided a large set of pathway activity with some significant overlap that may have translational relevance. Validation studies are currently on-going.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4919. doi:1538-7445.AM2012-4919
Abstract 4923: Understanding cancer invasion by the systems biological analysis of collective cell migration in 3D tissue models
Authors: Grabe Niels , Safferling Kai , Westphal Kathi , Guziolowski Carito , Kittas Aristotelis , Ernst Claudia , Halama Niels , Jaeger Dirk 
Published: August 2012

Abstract
Collective migration is essential for morphogenesis and wound repair in healthy tissue as well as for tissue invasion in cancer. In such migration cells move in supracellular, cadherin mediated units opposed to isolated ameoboid or mesenchymal movements. Understanding collective migration in healthy epithelia is a prerequisite for dissecting and analyzing invasion in carcinoma. We have set up a novel, easily reproducible 3D in vitro wound model of epidermal regeneration. The model is based on commercial tissue cultures and can thus be reproducibly manufactured in larger quantities. We used our model for a systematic analysis of wound reepithelialization by measuring cytokines and mRNA expression. Using virtual microscopy we could quantitatively capture the cellular intra-tissue streams during reepithelialization. We integrated our data in a systems biological multi-scale model. Our results uncover a sequence of different types of collective epithelial migration which occur during wound healing in an orchestrated manner. In cancer invasion these mechanisms are hijacked by the tumor in an emergent malignant exploit of the intrinsically healthy processes of epithelial morphogenesis and repair.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4923. doi:1538-7445.AM2012-4923
Abstract 493: Endothelin-1 induces activation of vascular endothelial growth factor receptor-3 and modulates cell migration and vasculogenic mimicry in melanoma cells
Authors: Spinella Francesca , Caprara Valentina , DiCastro Valeriana , Rosanò Laura , Cianfrocca Roberta , Natali Pier Giorgio , Bagnato Anna 
Published: August 2012

Abstract
Phenotypic and genotypic analyses of cutaneous melanoma have identified endothelin B receptor (ETBR) as tumor progression marker, thus representing a potential therapeutic target. We previously reported that the binding of ET-1 to ETBR stimulates angiogenesis and lymphangiogenesis directly and by stimulating vascular endothelial growth factor (VEGF)-A and VEGF-C production. In this study we investigated as to whether in melanoma cells ET-1 axis may interact with VEGF-A and VEGF-C signaling pathways to heighten cellular responsiveness. We found that in primary and metastatic melanoma cell lines, ET-1 increased VEGF-A, VEGF-C and its selective receptor VEGFR-3, at mRNA and protein level. Following ET-1 stimulation, VEGF-A and VEGF-C were upregulated, VEGFR-3 was rapidly phosphorylated and downstream signaling intermediates, such as p42/44 MAPK and Akt, were activated through ETBR. Inhibition of c-Src activity by PP2, reduced ET-1-induced VEGFR-3 phosphorylation, demonstrating that ET-1 transactivates VEGFR-3 through an intracellular mechanism mediated by c-Src. Stimulation with ET-1 in combination with VEGF-A or VEGF-C increased p42/44 MAPK and AKT phosphorylation, and resulted in a greater degree of melanoma cell migration compared to a single factor. Furthermore, this combination significantly enhanced the ET-1-induced vasculogenic differentiation of melanoma cells in capillary-like structures, vasculogenic mimicry, indicating that crosstalk between ET-1/ETBR axis with VEGFR-3/VEGF-C system may enhance cancer cell motility and invasiveness and contributes to the promotion of cancer metastasis. Finally, in melanoma xenografts, ETBR antagonist suppressed tumor growth and neovascularization-related effectors, indicating that targeting ETBR related signalling cascade may represent a novel treatment of melanoma by impairing the crosstalk between ET-1 axis and VEGF in melanoma. Supported by AIRC
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 493. doi:1538-7445.AM2012-493