bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1928: The lung microenvironment promotes stem-like phenotype and behavior of breast cancer cells
Authors: Sadri Ashkan , Allan Alison L. 
Published: July 2017

Abstract
Ninety percent of breast cancer-related mortalities result from metastasis, a process whereby the primary tumour disseminates and targets distant secondary organs. We have previously demonstrated that stem-like breast cancer cells expressing high levels of aldehyde dehydrogenase (ALDH) and CD44 are critical for metastasis. These ALDHhiCD44+ cells preferentially migrate and/or metastasize to the lung and bone microenvironments, where secondary tumours can severely impede organ function. However, the specific role of the lung and bone marrow (BM) microenvironments in supporting and/or promoting metastasis of ALDHhiCD44+ cells remains poorly understood, and this is the purpose of the current study. Using a 2D ex vivo model, lung and bone marrow (BM) conditioned media (CM) enriched in tissue-specific soluble proteins were generated from murine tissues and utilized in cell culture to assess their ability to influence the stem-like phenotype and behavior of MDA-MB-468 human breast cancer cells. Exposure to lung-CM promoted the generation of a viable, non-adherent (“floating”) breast cancer cell subpopulation that was not observed in response to BM-CM or basal media (p&lt;0.05). Phenotypic analysis by flow cytometry and gene expression analysis by RT-qPCR revealed notable differences in ALDH/CD44 phenotype in whole cell populations, adherent subpopulations, and/or non-adherent subpopulations in response to 72 hour exposure to lung-CM relative to basal media. In particular, the non-adherent breast cancer cell subpopulation generated in response to lung-CM demonstrated increased CD44 and ALDH1A3 gene expression and decreased ALDH1A1 gene expression relative to the adherent subpopulation (p&lt;0.05). No significant phenotypic or gene expression differences were observed in MDA-MB-468 breast cancer cells in response to BM-CM. Taken together with our previous studies, these findings suggest that while both the lung and bone microenvironments support breast cancer cells with a pre-existing ALDHhiCD44+ phenotype, the lung microenvironment may additionally help to even further promote stem-like phenotype and behavior in the secondary metastatic site. Ongoing studies are aimed at elucidating the mechanisms by which aggressive ALDHhiCD44+ breast cancer cells interact with and/or are influenced by the lung microenvironment during metastatic progression.
Citation Format: Ashkan Sadri, Alison L. Allan. The lung microenvironment promotes stem-like phenotype and behavior of breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1928. doi:10.1158/1538-7445.AM2017-1928
Abstract 1929: A novel orthotopic mouse model in sarcomas
Authors: Monclús Silvia Garcia , Martínez Juan Huertas , Tena Laura Lagares , Varona Santiago Rello , Rabaiget Olga Almacellas , Martin David Herrero , Alemany Roser López , Tirado Oscar Martinez 
Published: July 2017

Abstract
Pediatric sarcomas are a heterogeneous group of bone and soft tissue malignancies affecting children and young adults. One of the most important prognostic factors of those diseases is the presence of metastasis at diagnosis. In that context, we have developed a novel orthotopic model which consists in injecting Ewing Sarcoma (ES) or Rhabdomyosarcoma (RMS) tumor cells at the gastrocnemius muscle of mice and extracting the tumor at a of 10 mm x 13 mm volume. After surgery, animals maintain a complete functional extremity and can live until lung metastasis detection (about 60 days post-injection).
Moreover, we have validated the suitability of the model with an Ewing Sarcoma EphA2-low expression cell line. Epha2 is a tyrosine kinase receptor that has been found overexpressed in a wide variety of tumors and correlated with malignant phenotype. In this study we report that EphA2 receptor is phosphorylated at S897 in a panel of ES cell lines, which is related to the oncogenic properties of the receptor. Stable silencing of EphA2 in two different ES cell lines resulted in a decrease in the clonogenic, proliferation, migration and invasion capacity in vitro. Moreover, we performed an experimental metastasis assay, injecting tumor cells through the tail vain of mice and observed a reduction in the lung metastasis incidence in EphA2 silenced cells. We then used this new orthotopic metastasis model to validate the impairment in the invasion capacity of EphA2 silenced cells and confirm the decrease in lung metastasis incidence, indicating an oncogenic role for EphA2 in ES. This novel orthotopic metastasis model is a valuable tool both for the study of spontaneous metastasis and also for evaluating therapeutic index in the onset of metastasis, which can also be applied to the study of other pedriatric sarcomas.
Citation Format: Silvia Garcia Monclús, Juan Huertas Martínez, Laura Lagares Tena, Santiago Rello Varona, Olga Almacellas Rabaiget, David Herrero Martin, Roser López Alemany, Oscar Martinez Tirado. A novel orthotopic mouse model in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1929. doi:10.1158/1538-7445.AM2017-1929
Abstract 1937: Evolution of neuroblastoma patient-derived orthotopic xenografts through space and time
Authors: Braekeveldt Noémie , Fransson Susanne , Stedingk Kristoffer von , Öra Ingrid , Noguera Rosa , Martinsson Tommy , Nord David Gisselsson , Påhlman Sven , Bexell Daniel 
Published: July 2017

Abstract
Background Recently, we established orthotopic neuroblastoma patient-derived xenografts (PDXs) which maintain the phenotypic, genomic, and stromal hallmarks of patient tumors. Here we examined how PDXs evolve following years of in vivo growth.
Materials and Methods We established up to eight in vivo generations of neuroblastoma orthotopic PDXs through serial passaging in NSG mice. RNA sequencing, exome sequencing and SNP array analysis were used to analyze patient tumors and PDXs from different in vivo generations.
Results Using SNP analysis, we found mostly a remarkable genomic stability at chromosomal level between patient tumors, early and late PDX generations. RNA-seq revealed that patient tumors expressed higher levels of genes involved in immune responses and ECM metabolism compared to PDXs. Different PDX samples clustered correctly into their respective tumor type. PDXs from all early generations did not separate from PDXs from late generations. Thus, gene expression levels are surprisingly often quite stable despite years of in vivo growth. To shed light on neuroblastoma intratumor heterogeneity, we implanted 10 different tumor fragments from a single patient tumor into mice. We classified the 10 mice into three groups based on the time periods required for tumor growth. RNA-seq showed that each of these groups had a distinct gene expression profile and pathways involved in neuroblastoma progression have been identified.
Conclusions Neuroblastoma orthotopic PDXs are often very stable at chromosomal and gene expression levels despite years of in vivo growth. We utilized multiple PDXs to show functional intratumor heterogeneity coupled to distinct gene expression profile.
Citation Format: Noémie Braekeveldt, Susanne Fransson, Kristoffer von Stedingk, Ingrid Öra, Rosa Noguera, Tommy Martinsson, David Gisselsson Nord, Sven Påhlman, Daniel Bexell. Evolution of neuroblastoma patient-derived orthotopic xenografts through space and time [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1937. doi:10.1158/1538-7445.AM2017-1937
Abstract 1938: Exportin-1 (XPO1) is a novel therapeutic biomarker for patients with neuroblastoma
Authors: Galinski Basia , Luxemburg Marcus , Ewart Michelle , Landesman Yosef , Weiser Daniel 
Published: July 2017

Abstract
Background: Half of patients with high-risk neuroblastoma succumb to disease, yet these patients with inferior outcome cannot be identified at diagnosis despite contemporary risk stratification that integrates MYCN copy number status, tumor histology, and patient age. We have shown that overexpression of Exportin-1 (XPO1) is associated with poor survival in neuroblastoma, affirming what has been identified across a range of malignancies. Selinexor (KPT-330, Karyopharm Therapeutics), an XPO1 inhibitor in early phase clinical trials, inhibits the nuclear to cytoplasmic translocation of tumor suppressor and growth regulatory proteins implicated in oncogenesis. We hypothesized that protein expression level of XPO1 in neuroblastoma cell lines predict the effective response of treatment with selinexor.
Methods: We used a panel of early passage patient derived neuroblastoma cell lines including IMR5, NLF, KELLY, NB-EBC1, and SKNSH that are representative of the spectrum and genetic diversity of human disease. Cell lines were treated with varying concentrations of selinexor. RNA and whole cell protein extract as well as nuclear and cytoplasmic fractionated protein was obtained from untreated and treated conditions. Treated and untreated cells were also pelleted, and, along with patient tumor samples, formalin-fixed and paraffin-embedded for microscopic and immunohistochemical (IHC) evaluation.
Results: Compared to noncancerous cell lines, neuroblastoma cell lines have high protein and mRNA expression of XPO1; higher expression correlates with greater sensitivity to selinexor. Selinexor treatment reduced XPO1 protein and increased XPO1 mRNA expression, and it lead to nuclear retention of XPO1 cargo such as p53 and survivin. Comparison of microscopic features and protein staining intensity of patient samples with known XPO1 expression is ongoing.
Conclusions: This study provides rationale for XPO1 protein abundance as a potential biomarker of therapeutic response to the drug selinexor. By using patient derived neuroblastoma cell lines, we are able to evaluate the response of selinexor and XPO1 expression in the context of this enigmatic disease. These data suggest that initial drug response to selinexor can be predicted early in the course of disease and more investigation of the high expression of XPO1 seen in patients with poor outcome will provide strategies for combinatorial treatment approaches.
Citation Format: Basia Galinski, Marcus Luxemburg, Michelle Ewart, Yosef Landesman, Daniel Weiser. Exportin-1 (XPO1) is a novel therapeutic biomarker for patients with neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1938. doi:10.1158/1538-7445.AM2017-1938
Abstract 1939: Loss of MST/Hippo signaling promotes tumorigenesis in a genetically engineered mouse model of fusion-positive alveolar rhabdomyosarcoma
Authors: Oristian Kristianne , Crose Lisa E. , Bentley Rex , Kuprasertkul Nina , Kirsch David G. , Linardic Corinne 
Published: July 2017

Abstract
While improvement in survival for pediatric cancer patients over the last 40 years has been encouraging, certain cancer types evade cure. One such example is fusion-positive alveolar rhabdomyosarcoma (aRMS), a pediatric soft tissue sarcoma of mesenchymal origin with skeletal muscle features and a 5-year survival rate of &lt;50%. A hallmark of this aggressive malignancy is the t{2;13} translocation fusion gene PAX3-FOXO1 (PF). Primary cell-based modeling experiments in our laboratory and others have shown that PF is necessary but not sufficient for aRMS tumorigenesis, indicating additional molecular alterations are required to initiate and sustain tumor growth. Previously we showed that PF-positive aRMS tumorigenesis relies on alterations in Hippo pathway signaling, including upregulation of the YAP transcriptional co-activator, and downregulation of the MST/Hippo kinase, which occurs when the scaffold protein RASSF4 (itself a PF transcriptional target) binds and inhibits MST1/Hippo. We hypothesized that ablating MST/Hippo signaling in an existing genetically engineered mouse model (GEMM) of aRMS would accelerate tumorigenesis and provide insight into the role of this pathway in aRMS.
To assess the role of MST/Hippo signaling in aRMS, MST1/2-floxed (Stk3F/F;Stk4F/F) mice were crossed with an established MSTWT aRMS GEMM driven by conditional expression of Pax3-Foxo1 from the endogenous Pax3 locus and conditional loss of Cdkn2a in Myf6-expressing cells.
Statistical analysis revealed that compared to MSTWT aRMS control animals, MSTNull have significantly accelerated tumorigenesis (median survival 112 vs. 224 days, p&lt; 0.0001) and increased tumor penetrance (76% vs. 27%). MSTNull animals developed tumors disproportionately in the head and neck as compared to control, and incurred multiple tumors per animal. Tumors were analyzed via immunohistochemistry for MyoD and myogenin, markers of RMS, as well as Myf5, an early marker of myogenesis. Tumors in both cohorts were for positive for aRMS markers. Tumor-derived cell lines were used for in vitro cell-based assays and molecular interrogation.
We have identified the MST/Hippo signaling axis as an important tumor suppressor mechanism in aRMS. The rapid onset and increased penetrance of tumorigenesis in this GEMM provides a powerful tool for interrogating aRMS biology and screening novel therapeutics.
Citation Format: Kristianne Oristian, Lisa E. Crose, Rex Bentley, Nina Kuprasertkul, David G. Kirsch, Corinne Linardic. Loss of MST/Hippo signaling promotes tumorigenesis in a genetically engineered mouse model of fusion-positive alveolar rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1939. doi:10.1158/1538-7445.AM2017-1939
Abstract 1956: ABCE1 regulates the translational profile of neuroblastoma to drive tumor progression
Authors: Gao Jixuan , Somers Klaartje , Hannan Katherine M. , Fletcher Jamie I. , Liu Bing , Hannan Ross D. , Pearson Richard B. , Haber Michelle , Norris Murray D. , Henderson Michelle J. 
Published: July 2017

Abstract
Neuroblastoma is the most common extracranial solid tumor in children. A key driver of high-risk neuroblastoma is the MYCN transcription factor which fuels neuroblastoma progression by enhancing metabolic processes including protein translation (1). ABCE1, a member of the ATP-binding cassette (ABC) superfamily of transporters, is a translation factor directly up-regulated by MYCN (2). It is thought to dissociate the 80S ribosome into free 40S and 60S subunits so they can re-initiate translation and provide the protein building blocks required for rapid cell growth and migration (3). High ABCE1 expression is associated with poor clinical outcome in neuroblastoma patients (2). Therefore, we hypothesized that ABCE1 suppression may inhibit the aggressiveness of neuroblastoma by disabling protein synthesis. To test this, we suppressed ABCE1 using siRNAs in MYCN-amplified neuroblastoma cell lines, SK-N-BE(2) and CHP-134, which resulted in severely impaired cell migration (P&lt;0.001) and proliferation (P&lt;0.005). In mice xenografted with SK-N-BE(2) cells, ABCE1 suppression delayed tumor growth (P=0.001) and metastasis (P&lt;0.001). Mechanistically, when polyribosome analysis was used to monitor the impact of ABCE1 expression on protein translation in SK-N-BE(2) cells, loss of ABCE1 reduced the proportion of actively translating ribosomes (P&lt;0.001), leading to lower global protein synthesis (P=0.018). This is the first report of ABCE1 acting as pro-tumorigenic factor in neuroblastoma. Our data imply that targeting the translational machinery through ABCE1 may be an effective therapeutic approach for the treatment of MYC-driven cancers.
1.
Boon, K., Caron, H. N., van Asperen, R., Valentijn, L., Hermus, M. C., van Sluis, P., Roobeek, I., Weis, I., Voûte, P.A., Schwab, M. & Versteeg, R. (2001) EMBO J. 20, 1383-1393.
2.
Porro, A., Haber, M., Diolaiti, D., Iraci, N., Henderson, M., Gherardi, S., Valli, E., Munoz, M.A., Xue, C., Flemming, C., Schwab, M., Wong, J.H., Marshall, G.M., Della Valle, G., Norris, M.D. & Perini, G. (2010) J. Biol. Chem. 285, 19532-19543.
3.
Pisarev, A.V., Skabkin, M.A., Pisareva, V.P., Skabkina, O.V., Rakotondrafara, A.M., Hentze, M.W., Hellen C.U. & Pestova, T.V. (2010). Mol. Cell, 37, 196-210.
Citation Format: Jixuan Gao, Klaartje Somers, Katherine M. Hannan, Jamie I. Fletcher, Bing Liu, Ross D. Hannan, Richard B. Pearson, Michelle Haber, Murray D. Norris, Michelle J. Henderson. ABCE1 regulates the translational profile of neuroblastoma to drive tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1956. doi:10.1158/1538-7445.AM2017-1956
Abstract 196: Identification of small molecule inhibitors of the notch transcriptional activation complex
Authors: Astudillo Luisana , Capobianco Anthony 
Published: July 2017

Abstract
Deregulation of the Notch pathway underlies many aspects of cancer physiology depending on cell type and context. In many human cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype. Notch also plays a central role in cancer stem cells, which may underlie a role in metastasis and resistance to therapy. The important and diverse role played by Notch in cancer makes it an exceedingly attractive target for anti-neoplastic therapeutics. However, the full range of potential targets in the pathway have been under-explored. Through computer-aided drug design we explored potential ligand binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. An in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA was used for screening. We have recently reported the identification and characterization of a small molecule inhibitor of the Notch transcriptional activation complex, termed Inhibitor of Mastermind Recruitment-1 (IMR-1). Herein we report the characterization of small molecule inhibitors of Notch derived from IMR-1 that were identified through a combination of structure-activity relationship studies and molecular docking simulations. We demonstrate that these compounds inhibit the growth of Notch dependent cell lines and decrease Notch target gene transcription.
Citation Format: Luisana Astudillo, Anthony Capobianco. Identification of small molecule inhibitors of the notch transcriptional activation complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 196. doi:10.1158/1538-7445.AM2017-196
Abstract 1962: Regulation of invasion by lysine demethylase 5B in non-small cell lung cancer cells
Authors: Zoeller Elizabeth L. , Konen Jessica , Bell Joshua , Summerbell Emily , Kowalski Jeanne , Marcus Adam , Vertino Paula 
Published: July 2017

Abstract
Histone modifying enzymes are often dysregulated during carcinogenesis and are major contributors to the development of oncogenic features, including proliferation, drug resistance, and metastasis. Given these roles, histone modifiers are promising new targets for oncological therapeutics. One of the enzyme families at the center of this area of research is the lysine demethylase family KDM5, for which several inhibitors are in development. KDM5A and KDM5B are frequently overexpressed or mutated in human non-small cell lung cancer (NSCLC). In overexpression studies, KDM5B promotes invasion and migration of NSCLC cells, whereas invasion and migration of NSCLC cells were decreased following knockdown of KDM5B. Furthermore, in patients with NSCLC, KDM5B is expressed at higher levels in brain metastasis sites when compared to both normal tissues and primary tumors. These findings suggest a role for KDM5B in lung cancer and metastatic spread. However, the precise role of KDM5 family members in lung cancer invasion and metastasis is not known. Recently, we discovered that KDM5B is differentially expressed in cell subtypes within a 3D model of NSCLC collective cell invasion. In this model isolated single cells at the forefront of invasive branches (leader cells) express more 2-4 fold more KDM5B protein than the cells following (follower cells), while KDM5A and KDM5C are evenly expressed across both cell types. KDM5B mRNA expression is similar across cell types suggesting that the differential protein expression is mediated at the posttranscriptional level. Interestingly, global H3K4me3 levels are decreased in leader cells as compared to follower cells, supporting the idea that the lysine demethylases targeting this residue may be expressed at higher levels in leader cells. Collectively, these data suggest that KDM5B could be contributing to initiation of invasion at the primary site and thus, promoting metastasis. Given the rising prominence of therapeutic inhibitors of KDM5 family members, a better understanding how KDM5B contributes to cell invasion may lead to a new approach to the prevention of metastasis.
Citation Format: Elizabeth L. Zoeller, Jessica Konen, Joshua Bell, Emily Summerbell, Jeanne Kowalski, Adam Marcus, Paula Vertino. Regulation of invasion by lysine demethylase 5B in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1962. doi:10.1158/1538-7445.AM2017-1962