bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C56: microRNA-200 control of tumor cell cytoskeletal changes and invasion
Authors: Ungewiss Christin , Roybal Jonathon D. , Peng David H. , Gibbons Don L. 
Published: August 2014

Abstract
Lung cancer is the leading cause of all cancer-related deaths, accounting for 160,000 deaths per year in the US, primarily caused by metastasis. Understanding the molecular mechanisms leading to metastasis will identify new therapeutic targets for improved treatment strategies. Using our mutant Kras and p53 murine model of metastatic lung adenocarcinoma, we have shown that loss of microRNA-200 family (miR-200) expression is necessary and sufficient to drive an epithelial-to-mesenchymal transition (EMT), allowing cells to acquire an invasive and metastatic phenotype necessary for metastasis. Cell motility is characterized by the reorganization of the actin cytoskeleton, for which we are currently investigating the role of miR-200. Cortactin is a scaffold protein known to play a central role in different signaling pathways involved in the formation of pro-invasive cell structures by recruiting actin-associated proteins and proteases leading to the degradation of the extracellular matrix (ECM). Maturation of cell protrusions requires the phosphorylation of cortactin by upstream tyrosine kinases such as src and arg. Functional assay of cell behavior on 2D agarose demonstrates actin reorganization within our cell lines with different miR-200 levels. Biochemical analysis of cell lines from our model and human lung cancer cells shows that metastatic cells (low-miR-200) have increased levels of phosphorylated cortactin compared to the non-metastatic cells (high miR-200), leading us to hypothesize that miR-200 regulates the biochemical activation of signaling pathways that mediate cortactin phosphorylation and a pro-invasive cytoskeletal reorganization. Inhibition of src using pharmacologic inhibitors and an siRNA approach significantly reduces phosphorylated cortactin levels, inhibits in vitro cell migration and invasion, and decreases the invasiveness of cells grown in 3D, demonstrating the importance of this pathway in invasion. Furthermore, our study demonstrates that the pro-survival PI3K pathway can be inhibited using cortactin siRNA, underlining the multi-faceted role of cortactin in tumor progression.
Citation Format: Christin Ungewiss, Jonathon D. Roybal, David H. Peng, Don L. Gibbons. microRNA-200 control of tumor cell cytoskeletal changes 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 C56.
Abstract C57: The role of the microRNA-200 family in the regulation of tumor cell signaling and metastasis in lung cancer
Authors: Roybal Jonathon D. , Peng David H. , Ungewiss Christin , Mandal Pijus K. , McMurray John S. , Byers Lauren A. , Gibbons Don L. 
Published: August 2014

Abstract
Lung cancer is one of the deadliest cancers in the United States due primarily to the development of metastatic disease, resulting in a 16% five year overall survival. Unfortunately response rates are poor with the current modalities used to treat patients, which implies that a greater understanding of the biology of invasion and metastasis is essential. It is thought that the epithelial-mesenchymal transition (EMT) plays a critical role in regulating invasion, migration, and metastasis. The microRNA-200 family (miR-200) is a key maintenance factor for the epithelial phenotype by regulating EMT-inducing transcription factors such as Zeb1, and subsequent metastatic potential, although the mechanistic details of this regulation are incompletely understood. Recent research has demonstrated that miRNAs are capable of regulating the target mRNAs that coordinate intracellular signaling pathways. Using our mutant Kras and p53 murine model of metastatic lung adenocarcinoma, we have shown through reverse phase protein array (RPPA) profiling that in poorly metastatic lung tumor cells, high miR-200 levels can suppress cancer-promoting signaling molecules, such as Signal Transducer and Activator of Transcription 3 (STAT3). In contrast, highly metastatic lung tumor cells with low miR-200 expression have STAT3 activation and increased migratory and invasive properties. Utilizing siRNA approaches or pharmacological inhibition of STAT3 in highly metastatic lung tumor cells decreased their ability to migrate and invade. Our data suggests that the STAT3 pathway is under the control of miR-200/Zeb1 axis and could provide a potential therapeutic target in lung cancer patients.
Citation Format: Jonathon D. Roybal, David H. Peng, Christin Ungewiss, Pijus K. Mandal, John S. McMurray, Lauren A. Byers, Don L. Gibbons. The role of the microRNA-200 family in the regulation of tumor cell signaling and metastasis in lung cancer. [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 C57.
Abstract C59: Lipid expression dynamics in epithelial cells undergoing HGF-induced EMT
Authors: Alexander Kristen , Coutu Brendan , Prince John , Hansen Marc 
Published: August 2014

Abstract
Cancer metastasis occurs when cells detach from the primary tumor, invade through local tissues, migrate to distant sites, and colonize new tumors. The morphological change within the cell is termed epithelial-mesenchymal transition (EMT), as cells change from their epithelial state and derive more primitive, mesenchymal characteristics. A cellular signaling pathway that stimulates EMT is initiated by hepatocyte growth factor (HGF), which binds and activates the c-Met receptor tyrosine kinase. Activation of HGF signaling induces dramatic changes in cell morphology and behavior. HGF signaling exerts its effect by altering gene transcription and proteome profiles in cells triggered to undergo EMT. The proteomic changes in HGF-induced cell lines is well documented, however changes in lipid expression and their contribution to EMT are poorly understood. Here we develop and employ mass spectrometry-based approaches to analyze lipid expression changes in cells. This method allows for analysis of thousands of lipids in a single sample and the determination of the relative abundance in each lipid. We have found that seventy lipids undergo dramatic regulatory expression changes in MDCK cells undergoing HGF-induced EMT. This effort could provide important clues into the identity of lipid modification or synthesis programs that are required for EMT and, more broadly speaking, for cellular events associated with cancer progression. Understanding their contribution and function could allow for identification of therapeutic targets for intervention in cellular processes required for cancer metastasis.
Citation Format: Kristen Alexander, Brendan Coutu, John Prince, Marc Hansen. Lipid expression dynamics in epithelial cells undergoing HGF-induced EMT. [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 C59.
Abstract C64: Leptin increases the metastatic potential of breast cancer cells
Authors: Misrha Ameet , Blackburn Anneke C. , Parish Christopher R. , Wong Ma-li , Licinio Julio 
Published: August 2014

Abstract
In women, obesity is linked to 20% of all cancer deaths. The molecular mechanisms are largely unknown but the risk of invasive/metastatic disease with obesity may include elevated levels of hormones like leptin, IGFs and estrogens. Leptin is a pleiotropic hormone primarily synthesized by adipose tissues and circulating levels are higher in obese people (200ng/ml) than nonobese people (10ng/ml-30ng/ml). We examined the effect and mechanism of leptin treatment on the metastatic and cancer stem cell (CSC) characteristics of human breast cancer cells in vitro. Leptin receptor (LEPR) was found to be highly expressed in more invasive breast cancer cells (29-fold higher mRNA expression in MDA-MB-231 than MCF7, P&lt;0.0001). To assess the effect of leptin treatment on metastatic capacity of breast cancer cells, MCF7 cells were treated for 14 days with leptin. Compared to untreated MCF7 cells, treatment with 200ng/ml of leptin increased breast cancer cell motility (scratch assay, 1.85-fold, P=0.0018) and invasiveness (2.45-fold, P=0.0021). Leptin treatment induced epithelial to mesenchymal transition (EMT), decreasing CDH1 mRNA (0.1-fold, P=0.002) and increasing SNAI2 mRNA (4.1-fold, P&lt;0.0001) compared to the untreated cells. Leptin also induced aldehyde dehydrogenase activity by 6.4 fold (ALDEFLUOR, P=0.0069) and increased colony forming capacity (mammosphere assay, 2.03-fold, P&lt;0.0001) indicating an increased stem-like phenotype. Co-treatment of leptin and neutralizing antibody against TGFB1 abrogated these effects, indicating that the induction of EMT and CSC characteristics was mediated via TGFB1. This study indicates the significance of leptin in contributing to the poor outcomes of breast cancer in obese patients.
Note: This abstract was not presented at the conference.
Citation Format: Ameet Misrha, Anneke C. Blackburn, Christopher R. Parish, Ma-li Wong, Julio Licinio. Leptin increases the metastatic potential of breast cancer cells. [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 C64.
Abstract C76: Axl signaling is required for stem cell traits and metastasis in breast cancer
Authors: Tiron Crina , Pelissier Fanny , Wnuk-Lipinska Katarzyna , Stefansson Ingunn , Virtakoivu Reeta , Miyano Masaru , Sandal Tone , Micklem David , Garbe James , Stampfer Martha , Ivaska Johanna , Akslen Lars , LaBarge Mark , Lorens James 
Published: August 2014

Abstract
Epithelial-to-mesenchymal transition (EMT) endows carcinoma cells with migratory, survival and stem cell-like attributes that facilitate therapeutic resistance and metastasis. Expression of the Axl receptor tyrosine kinase in breast cancer correlates with EMT, poor survival and is prevalent in patient metastases. Axl upregulation in mammary epithelial cells by EMT-transcription factors, TGFbeta or hypoxia, establishes an autocrine-signaling loop with its ligand, Gas6. Inhibition of Axl signaling blocks EMT/ cancer stem cell traits including invasiveness, drug resistance, mammosphere formation, in vivo tumor initiation, and prevents spontaneous metastasis in orthotopic breast cancer models. Congruently, we show that Axl is expressed on mammary epithelial stem/progenitor cells and regulates multipotent progenitor activity. Thus Axl signal transduction represents a novel regulatory pathway linking normal mammary stem/progenitor cells and breast cancer stem cell activity. Clinical Axl-inhibitors represent a novel therapeutic opportunity to treat aggressive breast cancer.
Citation Format: Crina Tiron, Fanny Pelissier, Katarzyna Wnuk-Lipinska, Ingunn Stefansson, Reeta Virtakoivu, Masaru Miyano, Tone Sandal, David Micklem, James Garbe, Martha Stampfer, Johanna Ivaska, Lars Akslen, Mark LaBarge, James Lorens. Axl signaling is required for stem cell traits and metastasis in breast cancer. [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 C76.
Abstract C8: Bone metastasis seed preselection by the primary tumor stroma
Authors: Zhang Xiang , Jin Xin , Malladi Srinivas , Wen Yong , Brogi Edi , Massague Joan 
Published: August 2014

Abstract
A key question in understanding the origin of metastasis is how cancer cells in a primary tumor acquire the ability to colonize a distant organ. Here we provide one answer to this puzzle by proposing the “metastasis seed pre-selection” model: when the stroma of a primary tumor resembles that of a distant organ, it pre-selects cancer cells that are predisposed to survive in that organ. In breast cancer, the mesenchymal stromal components cancer-associated fibroblasts (CAFs) create a microenvironment similar to that of the bone marrow. Heterogeneous cancer cell populations growing in a CAF-rich breast tumor are skewed towards a preponderance of clones with a superior ability to survive and proliferate on the environmental cues CAFs produce. When these cancer cell clones metastasize and infiltrate the bone marrow, they can maximally exploit these cues familiar to them for initial survival. As a result, these cells have a better chance to colonize the bone when they metastasize. Thus, a CAF-rich stroma primes the breast tumor as a whole at risk of developing bone metastasis. Our findings have implications for the evolution of metastatic traits and the interplay between a primary tumor and its distant metastases.
Citation Format: Xiang Zhang, Xin Jin, Srinivas Malladi, Yong Wen, Edi Brogi, Joan Massague. Bone metastasis seed preselection by the primary tumor stroma. [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 C8.
Abstract C85: FOXM1-dependent gene expression program controls cancer stem cell and metastasis properties of breast cancer cells
Authors: Bergamaschi Anna , Madak-Erdogan Zeynep , Lu Hailing , Katzenellenbogen Benita S. 
Published: August 2014

Abstract
The transcription factor FOXM1 coordinates expression of late cell cycle-related genes. Elevated expression of FOXM1 in breast cancer correlates with a more aggressive tumor phenotype and, as we have previously shown, is associated with resistance to endocrine treatment via 14-3-3ζ protein signaling (Bergamaschi A. et al. Breast Cancer Research 2011, 13:R7). To better understand the role that FOXM1 plays in endocrine resistance and aggressiveness, we analyzed its genome-wide DNA binding and effects on gene expression. We mapped genome-wide FOXM1 binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in breast cancer cell lines after estrogen or tamoxifen treatments. We also investigated the relationship between FOXM1, estrogen receptor-α and MAPK chromatin binding events by clustering analysis of Chip-seq data and identified specific clusters of colocalized binding events as identifiers for different functional gene classes. Clusters enriched in colocalized factor binding sites were associated with genes involved in maintenance of stem cell properties and genes involved in invasion and metastasis (Rho-GTPases). Binding profiles were also integrated with expression data from FOXM1 knockdown experiments, to reveal specific FOXM1 transcriptional networks.
Cell studies showed the relevance of FOXM1 in breast cancer endocrine resistance and development of metastasis. We modulated the levels of FOXM1 and some newly discovered FOXM1 regulated genes in MCF7 cells and assessed their roles in hormone resistance and breast cancer aggressiveness by several functional studies. Increased expression levels of FOXM1 were associated with an increase in the cancer stem cell population. Moreover, FOXM1 overexpressing cell lines exhibited invadopodia which correlated with an increased invasion potential. The use of a specific and selective FOXM1 inhibitor proved to be especially effective in restoring endocrine sensitivity and in decreasing breast cancer aggressiveness. Collectively, our findings define FOXM1 as a master regulator of Rho-GTPase and stem cell marker expression. Dysregulation of the FOXM1 pathway promotes breast cancer progression and therefore makes FOXM1 a relevant therapeutic target to be considered for reducing invasiveness and enhancing response to endocrine and other therapies.
Citation Format: Anna Bergamaschi, Zeynep Madak-Erdogan, Hailing Lu, Benita S. Katzenellenbogen. FOXM1-dependent gene expression program controls cancer stem cell and metastasis properties of breast cancer cells. [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 C85.
Abstract C94: Systemic and stromal support of triple-negative breast cancer progression is prevented by EGF and IGF-1 inhibitors
Authors: Castano Zafira , Marsh Tim , Tadipatri Ramya , Kuznetsov Hanna S. , Al-Shahrour Fatima , Paktinat Mahanaz , Greene-Colozzi April , Nilsson Bjorn , Richardson Andrea L. , McAllister Sandra S. 
Published: August 2014

Abstract
By the time metastatic breast cancer is detected, patients are no longer treated with curative intent. Women with triple-negative breast cancer (TNBC) are particularly at risk for early recurrence. Clinical evidence indicates that in women with metastatic TNBC, the primary tumor and disseminated cells co-existed for an indefinite period of time. We demonstrate that outgrowth of distant tumors that would otherwise remain indolent in cancer-free mice is accelerated in mice with TNBC. Systemic signals provided by TNBCs cause formation of a tumor-supportive microenvironment at distant tumor sites. This microenvironment is enriched for EGF and IGF-1, which convert indolent tumors to a malignant state, defined by expression of factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Inhibition of both EGFR and IGF1R maintains these tumors in the indolent state. These results suggest that recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for TNBC patients.
Citation Format: Zafira Castano, Tim Marsh, Ramya Tadipatri, Hanna S. Kuznetsov, Fatima Al-Shahrour, Mahanaz Paktinat, April Greene-Colozzi, Bjorn Nilsson, Andrea L. Richardson, Sandra S. McAllister. Systemic and stromal support of triple-negative breast cancer progression is prevented by EGF and IGF-1 inhibitors. [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 C94.
Abstract C95: Correlated intrinsic breast cancer subtypes and expression of CD47 in BM predicts recurrence
Authors: Nagahara Makoto , Sugihara Kenichi , Mori Masaki 
Published: August 2014

Abstract
Purpose: The intrinsic breast cancer subtypes have shown the prognostic features. Focused on CD47 expression in bone marrow (BM), we previously demonstrated that CD47 is an important biomarker in breast cancer, and functions as a prognostic factor for DFS. The purpose of this study is to identify the correlation between breast cancer subtypes and CD47 expression in BM, which may indicate clinical implications.
Methods: Quantitative real-time PCR was used to evaluate CD47 mRNA expression in bone marrow (BM) and in peripheral blood (PB) from 738 cases of breast cancer. ER, PR, and Her2 scores were obtained from immunohistochemistry (IHC) staining, and Her2 FISH analysis conducted for IHC 2+.
Results: According to ER, PR, and Her2 statuses, the groups of Her2 enriched (ER- and PR- and Her2 3+) and triple negative(ER- and PR- and Her2-) were divided (n=38 and 72). The 5 years disease free survival rates in each subgroup were as followed: p=0.0004; ER+ and PR+ and Her2- 0.94, ER+ and/or PR+ or- and/or Her2+ or- 0.16, Her2 enriched 0.23, triple negative 0.34). In patients with high levels of CD47 expression in the BM, survival was significantly poorer compared to patients with low levels of CD47 expression (DFS of Her2 enriched group: P=0.003, DFS of triple negative group: P=0.002). Furthermore, high CD47 expression group in a multivariate analysis showed significance as an independent variable for poorer prognosis in DFS (P = 0.02). In the PB, however, high CD47 expression in patients was not an independent and significant prognostic factor for DFS and OS in a multivariate analysis.
Conclusions: We confirmed that overexpression of CD47 in BM correlated with the aggressiveness of Her2 enriched and triple negative subgroups. CD47 is a useful prognostic biomarker for predicting survival of Her2 enriched and triple negative subgroups in breast cancer. We suggest that high CD47 expression in BM may represent tumor dormancy in breast cancer involved in postsurgical recurrence and metastasis of Her2 enriched and triple negative subtypes.
Citation Format: Makoto Nagahara, Kenichi Sugihara, Masaki Mori. Correlated intrinsic breast cancer subtypes and expression of CD47 in BM predicts recurrence. [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 C95.
Abstract IA13: Niches and pathways of latent and overt metastasis
Authors: Massagué Joan 
Published: August 2014

Abstract
The signals and niches that allow disseminated tumor cells (DTCs) to stay viable as metastasis seeds are largely unknown. An understanding of these mechanisms is needed for the development of treatments to eradicate DTCs and prevent metastasis. We have identified molecular mechanisms that prime breast cancer DTCs for survival and stem cell fitness in distant organs. For survival, SRC primes DTCs for a robust PI3K-Akt response to CXCL12 and IGF1 in the bone marrow, and the leukocyte-tethering receptor VCAM-1 primes DTCs for PI3K-Akt activation by leukocyte contacts in the lungs. For stem cell fitness, the extracellular matrix protein tenascin-C (TNC) forms micrometastatic niches that promote WNT and NOTCH signaling. Additionally, a CXCL1-S100A8 paracrine loop protects DTCs from the stresses of metastasis and chemotherapy, providing a basis for these two clinically linked phenomena. In some cases, the pathways driving carcinoma formation additionally mediate metastasis. VHL inactivation leads to HIF signaling as a tumor-initiating event in clear cell renal carcinoma (ccRCC). However, VHL mutation status in ccRCC is not correlated with clinical outcome. We found that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis through CXCR4 and CYTIP. The strength of this activation is associated with poor clinical outcome. Thus, metastasis can be driven by an epigenetically expanded output of the tumor-initiating pathway as well as by events that are mechanistically uncoupled from the tumor-initiating pathway. In preclinical models, SRC kinase inhibitors, VCAM-1 blocking antibodies, and CXCL1 receptor inhibitors suppress metastasis and augment the efficacy of chemotherapy, providing new avenues for targeting DTCs in the adjuvant setting.
Citation Format: Joan Massagué. Niches and pathways of latent and overt 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 IA13.