tbuckley/cabot-search huggingface dataset:
Abstract 702: Serglycin promotes cell migration via modulating cytoskeleton reorganization and enhancing focal adhesion turnover
Authors: Jeou-Yuan Chen, Jing-You Guo
Journal: Cancer Research (2016)

Abstract Serglycin (SRGN), a hematopoietic cell granule proteoglycan, has recently been shown to be overexpressed in several aggressive cancer types. In nasopharyngeal and hepatocellular carcinomas, elevated expression of SRGN was shown to correlate with poor prognosis. However, the molecular mechanisms underlying SRGN-mediated malignancies remain to be explored. In this study, we showed that SRGN is expressed at elevated levels in several lung cancer-derived cell lines. By gain-of-function and loss-of-function approaches, we showed that SRGN promoted NSCLC cell migration. SRGN modulated actin cytoskeleton reorganization and promoted lamellipodia and filopodia formation at the leading edge, facilitating a directional movement during wound closure in NSCLC cells. In consistence, increased levels of activated Rac1, which is required for lamellipodia formation, and CDC42, which is required for filopodia formation, were detected. Increased focal adhesion (FA) turnover, the process of continuous assembly and disassembly of adhesions, would lead to increased cell migration. We further showed that SRGN promoted Src activation, leading to increased phosphorylation of paxillin (PAX) at Y118 as well as reduced PAX/FAK complex formation, which were well-defined indicators of FA turnover. Taken together, these data suggested that SRGN promotes cell migration through inducing cytoskeleton reorganization and focal adhesion turnover. Citation Format: Jeou-Yuan Chen, Jing-You Guo. Serglycin promotes cell migration via modulating cytoskeleton reorganization and enhancing focal adhesion turnover. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 702.
Abstract 1988: MYB overexpression is associated with castration-resistance in prostate cancer
Authors: Sanjeev K. Srivastava, Arun Bhardwaj, Seema Singh, Sumit Arora, Nikhil Tyagi, James E. Carter, Ajay P. Singh
Journal: Cancer Research (2016)

Abstract Clinical progression of prostate cancer (PCa) is characterized by a transition from castration-sensitive (CS) to castration-resistant (CR) phenotype. We previously demonstrated that MYB overexpression sustained the growth of PCa cells in androgen-depleted growth environment as well as promoted aggressive tumor phenotypes. Here, we examined its role in PCa progression and castration-resistance using appropriate mouse models and delineated underlying molecular mechanisms. Luciferase-tagged MYB-overexpressing (LNCaP-MYB) or -silenced (C4-2-shMYB) PCa cell lines along with their respective control sublines (LNCaP-Neo and C4-2-NTScr) were orthotopically implanted in nude mice and tumor growth was monitored by non-invasive bioluminescence imaging using Xenogen-IVIS optical system. Our data demonstrated significantly enhanced tumor growth in mice implanted with high MYB expressing (LNCaP-MYB and C4-2-NTScr) PCa cells as compared to low MYB expressing (LNCaP-Neo and C4-2-shMYB) cells. To study the role of MYB in castration-resistance, we castrated the mice after tumors from all groups reached comparable size as determined by in vivo imaging. Tumors in LNCaP-Neo and C4-2-shMYB groups exhibited drastic regression following castration. In contrast, only slight initial reduction in the tumor growth was reported in mice from LNCaP-MYB and C4-2-NTScr groups following castration, and they later regained tumor growth. Furthermore, Kaplan-Meier survival analysis revealed that the median survival of testis-intact (non-castrated) animals of LNCaP-Neo and C4-2-shMYB groups was significantly lower than that of castrated group mice. However, castration in high MYB-expressing tumor bearing mice could barely improve their median survival. Interestingly, MYB expression levels in orthotopic tumors correlated with serum PSA levels. Furthermore, castration of mice in LNCaP-Neo and C4-2-shMYB groups resulted in a rapid reduction in serum PSA levels; while it sustained and continued to rise in MYB overexpressing groups. In additional studies, we demonstrated that MYB interacts with androgen-receptor (AR) in prostate cancer cells, and facilitates the nuclear localization of AR in a ligand-independent manner. In essence, these results suggest a critical role of MYB in the CR progression of PCa. Citation Format: Sanjeev K. Srivastava, Arun Bhardwaj, Seema Singh, Sumit Arora, Nikhil Tyagi, James E. Carter, Ajay P. Singh. MYB overexpression is associated with castration-resistance in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1988.
Rituximab Plus Chlorambucil As Initial Treatment for Elderly Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Pre-Treatment Biological Characteristics and Gene Expression Patterns on Response to Treatment
Authors: Robin Foa, Stefania Ciolli, Francesco Di Raimondo, Giovanni Del Poeta, Francesco Lauria, Francesco Forconi, Antonio Cuneo, Agostino Cortelezzi, Francesco Nobile, Vincenzo Callea, Maura Brugiatelli, Massimo Massaia, Stefano Molica, Livio Trentin, Rita Rizzi, Giorgina Specchia, Lorella Orsucci, Achille Ambrosetti, Marco Montillo, Pier Luigi Zinzani, Felicetto Ferrara, Fortunato Morabito, Maria Angela Mura, Silvia Soriani, Marilisa Marinelli, Maria Stefania De Propris, Alessandra Alietti, Eva J. Runggaldier, Enrica Gamba, Ilaria Del Giudice, Silvia Bonina, Francesca Romana Mauro, Sabina Chiaretti, Anna Guarini
Journal: Blood (2011)
Abstract 1681: DUOX1 expression in lung cancer disrupts pro-oncogenic activation mechanisms and localization of Src and EGFR
Authors: Andrew C. Little, Karamatullah Danyal, Robert A. Bauer, David E. Heppner, Milena Hristova, Christopher Dustin, Aida Habibovic, Albert van der Vliet.
Journal: Cancer Research (2016)

Abstract Non-small cell lung cancer (NSCLC) remains to be one of the leading causes of cancer-related mortalities worldwide. The NADPH oxidase homolog, Dual Oxidase 1 (DUOX1), is an H2O2 producing enzyme located in the airway epithelium with key roles in mucosal host defense and wound repair mechanisms. Recent studies indicate that DUOX1 is epigenetically silenced in many forms of NSCLC via hypermethylation of its promoter. We previously demonstrated that DUOX1 silencing in lung cancer cells is associated with epithelial-to-mesenchymal transition (EMT), a key feature of tumor invasiveness and metastasis, and that RNAi-mediated DUOX1 suppression can promote EMT, but the mechanism(s) by which DUOX1 silencing promotes these outcomes are not understood. Previous findings indicate that DUOX1-dependent epithelial host defense pathways are mediated by redox-dependent activation of epithelial signaling via the non-receptor tyrosine kinase, Src, and the receptor tyrosine kinase, EGFR. We therefore hypothesized that loss of DUOX1 in lung cancer may be associated with aberrant regulation of Src and/or EGFR, tyrosine kinases that are frequently overexpressed and activated in lung cancer and strongly contribute to tumor growth and survival. Furthermore, nuclear Src/EGFR localization and phosphorylation of EGFR-Y1101 in lung cancers was recently associated with metastatic cell behavior and poor clinical outcome. Preliminary findings in alveolar lung cancer A549 cells, which possesses some EMT-like features, indicate that DUOX1 overexpression redistributes Src localization to the plasma membrane and decreases its nuclear accumulation. Moreover, DUOX1 overexpression in A549 cells also suppressed EGF-stimulated EGFR internalization and nuclear translocation, in association with reduced EGFR phosphorylation on its Src target, Y1101. Conversely, RNAi-mediated silencing of DUOX1 in the epithelial cancer cell line H292 (which has retained DUOX1 expression) promoted EGF-mediated EGFR nuclear translocation and Y1101 phosphorylation. Further mechanistic studies will be performed to elucidate the molecular mechanisms by which DUOX1 is able to alter these events. Collectively, our findings indicate that DUOX1 silencing in lung cancer may contribute to EMT and/or tumor invasiveness by altering Src/EGFR localization and activation mechanisms. Citation Format: Andrew C. Little, Karamatullah Danyal, Robert A. Bauer, David E. Heppner, Milena Hristova, Christopher Dustin, Aida Habibovic, Albert van der Vliet. DUOX1 expression in lung cancer disrupts pro-oncogenic activation mechanisms and localization of Src and EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1681.
Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study
Authors: S. Delaloge, D. Pérol, C. Courtinard, E. Brain, B. Asselain, T. Bachelot, M. Debled, V. Dieras, M. Campone, C. Levy, W. Jacot, V. Lorgis, C. Veyret, F. Dalenc, J.M. Ferrero, L. Uwer, P. Kerbrat, A. Goncalves, M.A. Mouret-Reynier, T. Petit, C. Jouannaud, L. Vanlemmens, G. Chenuc, T. Guesmia, M. Robain, C. Cailliot
Journal: Annals of Oncology (2016)
Abstract 1703: Expression of Hedgehog signals and growth inhibition by itraconazole in endometrial cancer
Authors: Kayo Inoue, Hiroshi Tsubamoto, Hiroaki Shibahara, Kazuo Tamura
Journal: Cancer Research (2016)

Abstract Background: There are limited therapeutic opportunities for the treatment of endometrial cancer (EC). Itraconazole, a common antifungal agent and a potent inhibitor of the Hedgehog pathway, has been shown to be clinically effective for various types of cancer, but its clinical efficacy for EC is unknown. Herein, we evaluated the efficacy of itraconazole in treating EC. Patients and Methods: We reviewed cases of patients with serous endometrial intraepithelial carcinoma (SEIC) and patients who were diagnosed with EC with endometrioid adenocarcinoma grade 1 or 2 at FIGO stage IA with myometrial invasion and negative cytology of ascites and who recurred at our institution from January 2005 to December 2013. We also reviewed cases with endometrioid adenocarcinoma grade 1 or 2 at FIGO stage IA with myometrial invasion and negative cytology of ascites without recurrence over 5 years after surgery during 2006 and 2007. Immunohistochemistry was performed on EC tumour samples including SEIC for sonic Hedgehog (sHh), glioma-associated oncogene homolog 1 (GLI1), Progesterone receptor (PR), and chemokine ligand 18 (CCL18). Furthermore, we examined the effects of itraconazole on human EC cell lines (Ishikawa and HEC-1A cells) using a modified methylthiazol tetrazolium (MTT) assay and a migration assay. Results: SHh and GLI1 were expressed in SEIC and endometrioid adenocarcinoma. Immunohistochemical evaluation of sHh and GLI1 did not distinguish between recurrent and non-recurrent low-grade FIGO stage IA EC. The MTT assay revealed that itraconazole significantly inhibited the growth of Ishikawa and HEC-1A cells in a dose-dependent and time-dependent manner. However, migration was not significantly effected for either Ishikawa or HEC-1A cells. HEC-1A cells exhibited dose-dependent migration retardation. Conclusion: Hedgehog signalling plays a role in carcinogenesis and malignant progression in EC. Itraconazole at a physiological dose may suppress progression of EC. Citation Format: Kayo Inoue, Hiroshi Tsubamoto, Hiroaki Shibahara, Kazuo Tamura. Expression of Hedgehog signals and growth inhibition by itraconazole in endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1703.
Abstract A33: Role for the tumor suppressor phf6 in hematopoiesis.
Authors: Finola E. Moore, Virginie Esain, Riadh Lobbardi, Jessica S. Blackburn, Trista E. North, David M. Langenau
Journal: Clinical Cancer Research (2015)

Abstract Plant Home domain Finger 6 (PHF6) is a tumor suppressor of unknown function for blood malignancies such as T-cell Acute Lymphoblastic Leukemia (T-ALL), Acute Myeloid leukemia (AML), and Chronic Myeloid Leukemia (CML). PHF6 contains two zinc finger-like PH domains and interacts with the Nucleosome Remodeling and Deacetylation (NuRD) complex, suggesting a role in chromatin remodeling. Although PHF6 loss-of-function mutations are found in nearly 40% of T-ALL patients, little is known about how PHF6 mutations contribute to blood development and leukemogenesis. To understand the function of PHF6, beginning with its role in hematopoiesis, we have undertaken developmental studies in zebrafish to discover how loss of phf6 affects blood development and to determine which pathways are regulated by phf6. Zebrafish will be used to study hematopoiesis due to the remarkable conservation of molecular pathways that regulate blood development, genetic tractability, and ability to observe embryonic development over a short window of time. RNA in situ hybridization studies of zebrafish embryos showed that phf6 is expressed broadly during zebrafish development, and especially in the dorsal aorta, a site analogous to the aorta-gonad-mesonephros (AGM) in mammals, from which hematopoietic stem cells (HSCs) arise. Further, phf6 is highly expressed in lymphocytes of adult zebrafish, reminiscent of the expression patterns found in human and mouse. To determine the effect of phf6 loss on hematopoiesis, phf6 expression was knocked down by morpholino injection. We find that phf6 morphants have increased numbers of HSCs by RNA in situ hybridization of runx1/cmyb in the AGM and caudal hematopoietic tissue ((CHT) analogous to mammalian fetal liver), sites of HSC emergence and migration. Later in development, phf6 morphants demonstrate increased lymphocytes by RNA in situ hybridization of rag1 at the thymus. Similar phenotypes were observed in homozygous phf6-null mutants generated by TALEN-mediated knockout. Phf6-null mutant zebrafish survive to Mendelian ratios and are fertile as adults. In total, we found a new role for phf6 in regulation of HSC formation. Citation Format: Finola E. Moore, Virginie Esain, Riadh Lobbardi, Jessica S. Blackburn, Trista E. North, David M. Langenau. Role for the tumor suppressor phf6 in hematopoiesis. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A33.
Abstract 436: Glycodelin expression in endometrial carcinoma
Authors: Hannu Koistinen, Annukka Pasanen, Laura Hautala
Journal: Cancer Research (2016)

Abstract Glycodelin is a lipocalin protein mainly expressed in well-differentiated epithelial cells in reproductive tissues, including endometrium and seminal vesicles. Previously, glycodelin has been shown to induce differentiation of endometrial carcinoma cells, which was associated with reduced xenograft tumor growth. Glycodelin is highly expressed in secretory endometrium, but not in proliferative or postmenopausal endometrium. While glycodelin is weakly, if at all, expressed in cancer tissues and, when expressed, associated with better prognosis, results regarding the expression of glycodelin in endometrial carcinoma are discordant. Therefore, we studied the expression of glycodelin in endometrial carcinoma and hyperplasia by immunohistochemical staining using highly validated antibody developed in house. Furthermore, the levels of mRNA were addressed utilizing in silico transcriptomics databases. Glycodelin transcripts were more abundant in normal uterus than in uterine carcinomas. Glycodelin staining in endometrial carcinoma sections was also much lower than that in secretory phase endometrium. Interestingly, in some endometrial hyperplasia samples glycodelin levels were much lower in hyperplastic regions of the sample as compared to those having normal histology. In conclusion, our data show that glycodelin is not highly expressed, if at all, in endometrial carcinoma tissues. This is in keeping with the reduced expression of glycodelin in postmenopausal endometrium and association of glycodelin in epithelial differentiation. Citation Format: Hannu Koistinen, Annukka Pasanen, Laura Hautala. Glycodelin expression in endometrial carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 436.
Abstract 4120: c-Met inhibition blocks MEK-induced tumor cell invasion in uveal melanoma
Authors: Oliver Surriga, Bryan D. Smith, Grazia Ambrosini, Daniel L. Flynn, Richard D. Carvajal, Gary K. Schwartz
Journal: Cancer Research (2016)

Abstract Uveal melanoma is the most common primary intraocular malignant tumor in adults. About half of patients with uveal melanoma will develop metastatic disease to the liver and the lung. These tumors are characterized by mutations in G-proteins (GNAQ and GNA11), activation of MAPK, and over-expression of c-Met. We have previously reported that c-Met inhibition inhibits tumor cell invasion and metastasis formation in uveal melanoma. Altiratinib is a selective inhibitor for c-Met as well as TIE2, VEGFR2 and TRK kinases. We found that this agent had no effect on inhibiting cell growth, consistent with our previous findings with crizotinib. However, it did inhibit invasion of uveal melanoma cells through matrigel in a concentration dependent fashion (25 nM to 250 nM) with inhibition of phospho-Met noted at concentrations as low as 25 nM. Selumetinib, a MEK inhibitor, is currently in clinical trial in patients with this disease. We found that treatment with 250 nM selumetinib inhibited cell proliferation but unexpectedly induced a marked increase in cell invasion of GNAQ and GNA11 mutant cell lines. This was associated with an increase in c-Met RNA and protein expression, as well as receptor phosphorylation, after 24 hours of selumetinib treatment. Combining selumetinib with altiratinib inhibited cell invasion to the level of altiratinib alone and continued to inhibit cell proliferation to the level of selumetinib alone. This effect was recapitulated by the knockdown of c-Met by siRNA prior to treatment with selumetinib. In a uveal melanoma xenograft model, the combination treatment of 15 mg/kg altiratinib and 25 mg/kg selumetinib significantly delayed tumor growth compared to vehicle control, altiratinib and selumetinib alone. Western blot analysis of tumor tissue confirmed target inhibition of p-Met and p-ERK in animals treated with altiratinib and selumetinib, respectively. Furthermore, tumor metastasis was inhibited by altiratinib, selumetinib and combination treatments in a uveal melanoma mouse model. These results indicate that the combined inhibition of MEK and c-Met by selumetinib and altiratinib, respectively, may be sufficient to suppress uveal melanoma tumor growth and metastasis. This strategy can potentially be used as therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease. Citation Format: Oliver Surriga, Bryan D. Smith, Grazia Ambrosini, Daniel L. Flynn, Richard D. Carvajal, Gary K. Schwartz. c-Met inhibition blocks MEK-induced tumor cell invasion in uveal melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4120.
Current anti-myeloma therapies in renal manifestations of monoclonal light chain-associated Fanconi syndrome: a retrospective series of 49 patients
Authors: M Vignon, V Javaugue, M P Alexander, K El-Karoui, A Karras, D Roos-Weil, B Royer, B Asli, B Knebelmann, G Touchard, A Jaccard, B Arnulf, F Bridoux, N Leung, J P Fermand
Journal: Leukemia (2016)
Abstract 186: Functional characterization of ERK3 mutants existing in human cancers
Authors: Hadel Alsaran, Lobna Elkhadragy, Weiwen Long
Journal: Cancer Research (2016)

Abstract Extracellular signal-Regulated Kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family. Recent studies have shown that ERK3 is highly upregulated in multiple cancers, such as lung cancer and colon cancer, and plays an important role in promoting cancer migration and invasion. While the link between ERK3 and cancers has been recognized, little is known about ERK3 mutations in cancer progression. In this study, we have investigated ERK3 mutations on R64 and L290 that have been found in cancers of lung, large intestine and skin (COSMIC database). Importantly, mutations of R64C, R64H, L290P and L290V all are located in the kinase domain of ERK3. In order to characterize these mutations, we generated ERK3 mutants with each of these point mutations, and then overexpressed them in HeLa cells with or without stable knockdown of endogenous ERK3. Notably, we found that in comparison with wild type ERK3, all of these cancer-related mutations lead to reduction of phosphorylation at S189 within the activation loop (an indicator of ERK3 kinase activity). While activation loop phosphorylation is well known to result in activation of the classical MAPKs, its effects on the activity and functions of ERK3 remain elusive. To study the functional impact of these ERK3 mutations on cancer cell invasiveness, we performed trans-well migration assays using HeLa cells overexpressing each of these mutants or the wild type ERK3. In line with previous finding, overexpression of ERK3 increased cell migration. Interestingly, both L290P and L290V mutations significantly increased ERK3's ability in promoting cell migration, whereas R64C and R64H mutations resulted in a decrease in cell migration. These results suggest that S189 phosphorylation within the activation loop does not correlate with ERK3's function in promoting cancer cell motility. To conclude, we report for the first time the functional characterization of cancer-related ERK3 mutations in modulating cancer cell migratory properties. Citation Format: Hadel Alsaran, Lobna Elkhadragy, Weiwen Long. Functional characterization of ERK3 mutants existing in human cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 186.
A Ph 1B Study of the Anti-Cancer Stem Cell Agent Demcizumab (Dem) &amp; Gemcitabine (Gem) +/- Paclitaxel Protein Bound Particles (Nab-Paclitaxel) in Pts with Pancreatic Cancer
Authors: M. Hidalgo, M. Jameson, A. Carrato, P. Cooray, F. Parnis, P. Grimson, G.M. Jeffery, R. Stagg, J. Dupont, N. Tebbutt
Journal: Annals of Oncology (2014)