bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A66: NEDD9 promotes cell invasion through modulation of ARF6 activity and endocytic recycling
Authors: Pugacheva Elena N. , Loskutov Yuriy , McLaughlin Sarah , Kozyulina Polina , Kozyreva Varvara , Ice Ryan , Culp Mark , Wysolmerski Robert , Weed Scott , Ivanov Alexey 
Published: August 2014

Abstract
The adhesion scaffolding protein NEDD9 was identified as potential pro-metastatic gene in several cancers. The molecular mechanisms of NEDD9-driven metastasis are still unknown. In this study, we show that expression of NEDD9 positively correlates with the invasive stage of breast cancer. We show that NEDD9 localizes to invadopodia and endosomes. Notably, NEDD9 depleted cells have increased levels of inactive surface receptors due to increase in fast recycling of Rab4 and Rab5 positive vesicles. Mechanistically, we found that NEDD9 binds to and scaffolds the Arf6 specific GAP - ASAP3, decreasing Arf6 activity. Thus, depletion of NEDD9 leads to activation of Arf6. Inhibition of Arf6 or re-expression of NEDD9 in shNEDD9 cells was sufficient to restore recycling rates, decrease the number of Rab4 and 5 positive vesicles and the invasive properties of tumor cells. Thus, in this work, we uncover the mechanistic basis of NEDD9-driven invasion and identify a new role for NEDD9 in Arf6-dependant endocytosis.
Citation Format: Elena N. Pugacheva, Yuriy Loskutov, Sarah McLaughlin, Polina Kozyulina, Varvara Kozyreva, Ryan Ice, Mark Culp, Robert Wysolmerski, Scott Weed, Alexey Ivanov. NEDD9 promotes cell invasion through modulation of ARF6 activity and endocytic recycling. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A66.
Abstract A69: aB-crystallin: A novel regulator of breast cancer metastasis to the brain
Authors: Malin Dmitry , Strekalova Elena , Ugolkov Andrey , Petrovic Vladimir , Cryns Vincent 
Published: August 2014

Abstract
Brain metastases are a devastating complication of advanced breast cancer that result in disabling neurologic deficits and death within one year in the vast majority of patients. Triple-negative breast tumors, which lack expression of the estrogen receptor, progesterone receptor and HER2, commonly metastasize to the brain. However, the genes regulating brain metastasis are poorly understood. The molecular chaperone aB-crystallin is frequently expressed in triple-negative breast cancer and has been reported to play important roles in cytoskeletal organization, cell migration and invasion. As such, we hypothesized that aB-crystallin promotes metastasis in triple-negative breast cancer. To test this hypothesis, we stably overexpressed aB-crystallin in triple-negative breast cancer cells with low endogenous expression of the protein and stably silenced aB-crystallin in triple-negative breast cancer cells with high endogenous levels. We examined the effects of altering aB-crystallin levels on adhesion to human brain microvascular endothelial cells (HBMECs) and penetration of an in vitro model of the blood-brain barrier (BBB). In addition, orthotopic models of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to the brain were utilized to evaluate the effects of aB-crystallin on primary and metastatic tumor burden in vivo. We observed that silencing aB-crystallin inhibited adhesion to HBMECs and penetration of an in vitro BBB model, while overexpression of aB-crystallin enhanced adhesion to HBMECs and penetration of the BBB in vitro. Consistent with these results, overexpression of aB-crystallin in triple-negative breast cancer cells increased brain metastasis in female NSG mice with transplanted mammary tumors, while silencing aB-crystallin inhibited brain metastasis. We also demonstrated that aB-crystallin enhanced adhesion to HBMECs by a b1 integrin-dependent mechanism. Taken together, our results point to a novel role of aB-crystallin in breast cancer brain metastasis and suggest that aB-crystallin may be a promising drug target for this rapidly fatal disease.
Citation Format: Dmitry Malin, Elena Strekalova, Andrey Ugolkov, Vladimir Petrovic, Vincent Cryns. aB-crystallin: A novel regulator of breast cancer metastasis to the brain. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A69.
Abstract A7: Neural regulation of metastasis: New avenues for therapeutic intervention
Authors: Le Caroline P. , Lamkin Donald , Chai Ming G. , Kim Corina , Pimentel Matthew A. , Cole Steven W. , Sloan Erica K. 
Published: August 2014

Abstract
Recent clinical and experimental studies demonstrated that the neuroendocrine system accelerates cancer development and progression. To investigate the cellular and molecular mechanism of neuroendocrine regulation of cancer, we have used advanced in vivo imaging technologies to investigate spatial relationships between peripheral neural system, tumor cells and the metastatic microenvironment. We found that chronic activation of the sympathetic nervous system accelerates breast cancer metastasis to distant tissues. Increased metastasis was dependent on beta-adrenergic signaling which induced macrophage recruitment to primary tumors and induced a switch to pro-metastatic and pro-inflammatory gene expression. Our recent studies in orthotopic xenograft models of pancreatic cancer and leukemia showed that activation of neural stress-response pathways similarly accelerated disease progression, suggesting that adrenergic signaling may be a general physiological regulator of cancer progression. These findings raise the possibility that beta-blockade of neural stress response pathways may be a novel therapeutic strategy to slow or prevent metastasis. In addition, we will discuss findings that targeting peripheral nerve fibers may provide therapeutic leverage against metastasis.
Citation Format: Caroline P. Le, Donald Lamkin, Ming G. Chai, Corina Kim, Matthew A. Pimentel, Steven W. Cole, Erica K. Sloan. Neural regulation of metastasis: New avenues for therapeutic intervention. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A7.
Abstract A73: In vivo evidence of TIMPv as a potential target of CD146-signaling inhibiting breast tumor invasion
Authors: Ouhtit Allal , Elmageed Zakariya Y. Abd , Bhat Sunil , Raman Pravrutha , Al-Jardani Suad H. , Gupta Ishita , Shanmuganathan Somya , Al-Riyami Hamad 
Published: August 2014

Abstract
CD146, also known as melanoma cell adhesion molecule (Mel-CAM, MCAM) or MUC18, was initially identified as a marker of melanoma progression and a promoter of melanoma and prostate cancer (PC) metastasis. In contrast, CD146 appears to play a tumor suppression role in breast cancer (BC). Here, we applied microarray gene expression profiling analysis, using a tetracycline (tet On)-inducible system of CD146 in the MDA-MB-231 BC cell line, and we identified TIMPv (a variant of Tissue Inhibitor of Metalloproteinases), showing a 7 fold increase, as a potential CD146-downstream signaling transcriptional target; this was confirmed in vitro by both time-course western blotting and RT-PCR. Furthermore, breast tumor tissues from both Omani patients and patients from New Orleans area in Louisiana, were examined by immunohistochemistry for the expression of CD146 and TIMPv. Strikingly, the results revealed that the expression levels of both CD146 and its downstream target TIMPv showed parallel inhibition patterns in BC progression, with high expression in normal and benign but low or no expression in malignant and metastatic breast tumor tissue. These findings support the hypothesis that the expression of both, CD146 and its downstream target TIMPv, is lost during BC progression and metastasis. Ongoing studies in our laboratory aim to shed light on the molecular components linking CD146 to the activation of TIMPv transcription.
Citation Format: Allal Ouhtit, Zakariya Y. Abd Elmageed, Sunil Bhat, Pravrutha Raman, Suad H. Al-Jardani, Ishita Gupta, Somya Shanmuganathan, Hamad Al-Riyami. In vivo evidence of TIMPv as a potential target of CD146-signaling inhibiting breast tumor invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A73.
Abstract A76: FGF-2 accelerates TGF-β-induced epithelial-mesenchymal transition
Authors: Saitoh Masao , Shirakihara Takuya , Miyazawa Keiji 
Published: August 2014

Abstract
Epithelial mesenchymal transition (EMT) is a crucial event in appropriate embryonic development as well as in wound healing, tissue repair, and cancer progression in adult tissues. EMT endows cells with migratory and invasive properties, inhibits apoptosis and senescence, contributes to immunosuppression, and induces stress resistance and stem cell properties. We have recently demonstrated that transforming growth factor (TGF)-β induces isoform switching of fibroblast growth factor (FGF) receptors through regulating expression of epithelial splicing regulatory proteins 1 and 2, and thereby FGF-2 promotes EMT in collaboration with TGF-β. We performed a microarray analysis to elucidate changes in expression profiles during the enhanced EMT by combined treatment of TGF-β with FGF-2, and found that several genes are specifically upregulated by the combined treatment. Here, roles of these genes in the enhanced EMT by TGF-β and FGF-2 will be discussed.
Citation Format: Masao Saitoh, Takuya Shirakihara, Keiji Miyazawa. FGF-2 accelerates TGF-β-induced epithelial-mesenchymal transition. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A76.
Abstract A77: Transmembrane 4 L six family member 5 (TM4SF5) regulates FAK/c-Src signaling activity for cell migration and invasion
Authors: Jung Oisun , Choi Yoon-Ju , Lee Jung Weon 
Published: August 2014

Abstract
Transmembrane 4 L six family member 5 (TM4SF5) is a transmembrane glycoprotein of the transmembrane 4 L six family and highly expressed in many types of cancers. In addition to diverse tumorigenic functions, TM4SF5 also plays roles in migration and invasion, leading to lung metastasis of TM4SF-positive cells injected into tail veins. To understand the TM4SF5-mediated metastatic roles, we mechanistically explored TM4SF5-mediated signaling pathways for migration and invasion. Using endogenously or exogenously TM4SF5-null or -expressing hepatocytes in vitro and mouse animals in vivo, we revealed how TM4SF5 mediated the metastatic processes along the leading edges of migratory/invasive cells. The intracellular loop of TM4SF5 directly and adhesion-dependently bound FAK with causing a structural alteration possibly to release the inhibitory intramolecular interaction, which activated FAK at the leading edges of cells to promote migration/invasion and in vivo metastasis. Impaired interactions between TM4SF5 and FAK attenuated phospho-FAK, signaling link to actin organization machinery, and metastatic potentials. Meanwhile, the cytosolic C-terminus of TM4SF5 bound c-Src that led to invasive protrusion formation. Wildtype TM4SF5 expression enhanced invasive protrusion formation in a c-Src-dependent manner, compared with TM4SF5-null control hepatocytes, but tailless TM4SF5ΔC cells were more efficient than were wildtype TM4SF5 cells, suggesting a negatively regulatory role by its C-terminus. c-Src activity of TM4SF5 WT- or TM4SF5ΔC-expressing cells EGF-independently correlated with enhanced phospho-Tyr845 in EGFR for the invasive protrusions. Altogether, this study suggests that TM4SF5 is involved in signaling for migration and invasion and is a promising target for the treatment of TM4SF5-positively metastatic cancer.
Citation Format: Oisun Jung, Yoon-Ju Choi, Jung Weon Lee. Transmembrane 4 L six family member 5 (TM4SF5) regulates FAK/c-Src signaling activity for cell migration and invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A77.
Abstract A78: MUC1 drives c-Met-dependent migration and scattering
Authors: Horm Teresa M. , Bitler Benjamin G. , Broka Derrick M. , Louderbough Jeanne , Schroeder Joyce A. 
Published: August 2014

Abstract
The transmembrane mucin MUC1 is overexpressed in most ductal carcinomas, and its overexpression is frequently associated with metastatic progression. MUC1 can drive tumor initiation and progression via interactions with many oncogenic partners, including β-catenin, the epidermal growth factor receptor (EGFR) and Src. The decoy peptide PMIP (Protein transduction domain MUC1 Inhibitory Peptide) has been shown to inhibit the tumor promoting activities of MUC1 in breast and lung cancer, including cell growth and invasion, and its usage suppresses metastatic progression in mouse models of breast cancer. To further characterize the reduced metastasis observed upon PMIP treatment, we performed motility assays and observed that PMIP inhibits cell motility of breast cancer cells. To determine the mechanism by which PMIP inhibits motility, we evaluated changes in global gene transcription upon PMIP treatment, and identified a number of genes with altered expression in response to PMIP. Among these genes is the metastatic mediator, c-Met, a transmembrane tyrosine kinase that can promote cell scattering, migration and invasion. To further investigate the role of c-Met in MUC1-dependent metastatic events, we evaluated the effects of MUC1 expression and EGFR activation on breast cancer cell scattering, branching and migration. We found that MUC1 strongly promoted all of these events and this effect was further amplified by EGF treatment. Importantly, the effect of MUC1 and EGF on these phenotypes was dependent upon c-Met activity. Overall, these results indicate that PMIP can block the expression of a key metastatic mediator, further advancing its potential use as a clinical therapeutic.
Citation Format: Teresa M. Horm, Benjamin G. Bitler, Derrick M. Broka, Jeanne Louderbough, Joyce A. Schroeder. MUC1 drives c-Met-dependent migration and scattering. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A78.
Abstract A79: Elucidating the role of E2F2 transcription factor in mediating human breast cancer metastasis
Authors: Yuwanita Inez , Barnes Danielle , Andrechek Eran 
Published: August 2014

Abstract
In human breast cancer metastasis, it is not the primary tumor that is the cause of mortality but metastasis to distant sites. Therefore, it is important to elucidate the biological mechanism that underlies the metastatic processes. To address this, we utilized bioinformatic methods in combination with biochemical assays and genetic studies. Specifically, we crossed a MMTV-Myc mouse model with various activator E2Fs mutants and found that the tumor incidence decreased in the MMTV-Myc mice crossed with E2F2 and E2F3 mutant background. Surprisingly, we also found that the loss of E2F2 sharply increased lung metastasis in MMTV-Myc mice. Here, we test whether these observations in mice translate to human breast cancer and identify the genes under the control of E2F2 transcription factor that are responsible for mediating breast cancer metastasis. To achieve these aims, we examined the probability of activation of the E2F2 transcription factors in human breast cancer. We calculated the probability of E2F2 activation and used this data to stratify the human breast cancer samples and their associated metastatic clinical data. We performed hierarchical clustering of human and mouse gene expression datasets and uncovered two clusters of human breast tumors in which E2F2 played distinctly different roles in mediating metastasis. The human breast cancer samples that clustered with our mouse gene expression data exhibited the same role for E2F2 whereby it increased time to distant metastasis. We then examined genes that were differentially regulated within this cluster and found that there was a set of genes that were associated with a difference in human metastasis survival times and with the E2F2 knockout in the mouse model. To further explore the mechanism by which E2F2 mediates human breast cancer metastasis, we have identified four genes asputative E2F2 target genes including KLK1, MYH2, PTPRD and TNNC2. We found that partial knockdown of KLK1 promotes the migratory capacity of MCF7 cell in vitro. In addition, partial knockdown of PTPRD affected cellular morphology, where they were found to grow in discreet clusters while having little effect on the migration capacity in a scratch assay. We are currently exploring the effects of MYH2 and TNNC2 ablation on these cells. Taken together, we have begun to elucidate the roles of E2F2 transcription factor in mediating breast cancer metastasis as well as establishing a mechanism by which E2F2 regulates metastasis.
Citation Format: Inez Yuwanita, Danielle Barnes, Eran Andrechek. Elucidating the role of E2F2 transcription factor in mediating human breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A79.
Abstract A84: Synaptojanin-2 and microRNA-31 control invadopodia and metastasis by regulating vesicular trafficking
Authors: Ben-Chetrit Nir , Chetrit David , Koerner Cindy , Carvalho Silvia , Symons Marc , Schmitt Fernando , Wiemann Stefan , Ehrlich Marcelo , Yarden Yosef 
Published: August 2014

Abstract
Growth factors propel cell migration and metastasis, but underlying mechanisms are incompletely understood. Employing EGF-stimulated mammary cells we link the lipid phosphatase synaptojanin 2 (SYNJ2) to an invasive phenotype, and relate high SYNJ2 and low microRNA-31, a metastasis suppressor that restrains SYNJ2, to short survival rates of cancer patients. Knockdown of SYNJ2 robustly impaired both intravasation and extravasation of mammary tumor cells in an animal model. In vitro, SYNJ2-depleted cells exhibited derailed trafficking of EGFR and integrins, resulting in deformed focal adhesions, arrested lamellipodia and disappearance of invadopodia. We conclude that recycling of active EGFRs focally promotes SYNJ2-mediated dephosphorylation of specific phosphoinositol lipids, thereby instigates formation of both invadopodia and lamellipodia and facilitates tumor progression.
Citation Format: Nir Ben-Chetrit, David Chetrit, Cindy Koerner, Silvia Carvalho, Marc Symons, Fernando Schmitt, Stefan Wiemann, Marcelo Ehrlich, Yosef Yarden. Synaptojanin-2 and microRNA-31 control invadopodia and metastasis by regulating vesicular trafficking. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A84.
Abstract A86: SIRT1 regulates Rac1-GTPase activation via the guanine nucleotide exchange factor TIAM1
Authors: Saxena Madhurima , Dykes Samantha S. , Wang Allison E. , Cardelli James A. , Pruitt Kevin 
Published: August 2014

Abstract
SIRT1 deacetylase is overexpressed in different types of cancers and we and a few others have described a role for SIRT1 in regulating cancer cell migration. Rho GTPases are classic regulators of cell motility and are known to aberrantly enhance cancer cell migration in response to several anomalous cues. We hypothesized that one of mechanisms employed by SIRT1 to regulate cell motility is through regulation of Rac1-GTPase activation.
To address this we utilized two cancer cell lines, CFPAC-1 pancreatic and MDA-MB-231 breast cancer cells, as our model. A significant decrease was observed in active Rac1 (GTP-bound Rac1) levels, in a GST-PAK-binding domain pull-down assay, upon inhibition of SIRT1 by small molecule inhibitors or knockdown of SIRT1 by shRNA as compared to vehicle-treated or non-targeting shRNA transfected cells. Subsequent analysis revealed that SIRT1 co-immunoprecipitated with the Rac-guanine nucleotide exchange factor (GEF), TIAM1. To test whether TIAM1 is acetylated and if SIRT1 regulates its deacetylation we performed antibody-based pull-down of acetylated lysines from whole cell protein extracts and observed TIAM1 acetylation. Inhibition of deacetylase activity by small molecule inhibitors or overexpression of acetyltransferases caused an enhancement of acetylated TIAM1 signal. While a change in TIAM1 localization was not observed with SIRT1 knockdown, its ability to activate Rac1 was compromised.
Several studies have demonstrated SIRT1's pro-tumorigenic potential. In this study we elucidate a mechanism by which SIRT1 regulates Rac-GTPase activation via TIAM1 acetylation. Controlling the “switch-mechanism” that the small GTPases utilize for inducing downstream activity can be crucial from a drug-development perspective. Our findings not only provide a new mechanism for regulation of Rac-GTPase activity but also emphasize SIRT1's potential as a targetable molecule in cancer.
This work is supported by CA155223 and the graduate stipend for Madhurima Saxena is provided by a Carroll-Feist Pre-doctoral Fellowship awarded by the Feist-Weiller Cancer Center at LSU Health Shreveport, Shreveport, LA.
Citation Format: Madhurima Saxena, Samantha S. Dykes, Allison E. Wang, James A. Cardelli2,3, Kevin Pruitt1,3. SIRT1 regulates Rac1-GTPase activation via the guanine nucleotide exchange factor TIAM1. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A86.