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In the Metastatic Dissemination of Medulloblastoma Published OnlineFirst October 5, 2010; DOI: 10.1158/0008-5472.CAN-10-0592 Published OnlineFirst on October 5, 2010 as 10.1158/0008-5472.CAN-10-0592 Therapeutics, Targets, and Chemical Biology Cancer Research Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma Christopher Traenka1, Marc Remke2,5, Andrey Korshunov4,6, Sebastian Bender2,5, Thomas Hielscher3, Paul A. Northcott7, Hendrik Witt2,5, Marina Ryzhova8, Jörg Felsberg9, Axel Benner3, Stephanie Riester2, Wolfram Scheurlen10, Thomas G.P. Grunewald11, Andreas von Deimling6, Andreas E. Kulozik5, Guido Reifenberger9, Michael D. Taylor7, Peter Lichter2, Elke Butt1, and Stefan M. Pfister2,5 Abstract Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immuno- histochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA–mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medullo- blastoma. Cancer Res; 70(20); 8003–14. ©2010 AACR. Introduction fluid cytology, is a powerful prognostic marker in medullo- blastoma (2, 3). Brain tumors and leukemias comprise the most common Molecular signaling pathways involved in the patho- cause of cancer-related mortality in children with medullo- genesis of standard-risk medulloblastoma such as the blastoma being the most common malignant brain tumor WNT and sonic hedgehog (SHH) signaling cascades are in this age group (1). The presence of leptomeningeal dissem- well-established (4–6), whereas the molecular biology ination at diagnosis detected either macroscopically by underlying intermediate and high-risk medulloblastoma craniospinal imaging or microscopically by cerebrospinal remains elusive. Aberrant activation of WNT signaling, typically caused by activating CTNNB1 mutations (and rarely APC or AXIN), followed by nuclear accumulation of CTNNB1 Authors' Affiliations: 1Institute of Clinical Biochemistry and Pathobiochemistry, protein as first described by Ellison and colleagues (7), is University of Wuerzburg, Wuerzburg, Germany; Divisions of 2Molecular now commonly accepted as the hallmark genetic event for Genetics and 3Biostatistics, 4Clinical Cooperation Unit Neuropathology, – German Cancer Research Center (DKFZ); Departments of 5Pediatric standard (or low) risk medulloblastoma (8 10). The WNT Oncology, Hematology & Immunology and 6Neuropathology, University subgroup of tumors may be cytogenetically identified by of Heidelberg, Heidelberg, Germany; 7Division of Neurosurgery, and Program the presence of monosomy 6, which is exclusively found in in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; 8NN Burdenko Neurosurgical Institute, Moscow, Russia; tumors of this subset (4, 6, 8, 11). A second distinct sub- 9Department of Neuropathology, Heinrich-Heine-University, Dusseldorf, group of standard-risk patients identified by transcriptome Germany; 10Cnopf'sche Kinderklinik, Nürnberg Children's Hospital, – Nuremberg, Germany; and 11Department of Pediatrics and Childrens' studies (4 6) is molecularly characterized by aberrant SHH Cancer Research Center, Klinikum rechts der Isar, Technische Universität activation, and is typically driven by underlying mutations München, Munich, Germany in key regulators of the pathway such as PTCH1 or SUFU Note: Supplementary data for this article are available at Cancer Research (12–14). Collectively, these two subgroups account for ap- Online (http://cancerres.aacrjournals.org/). proximately 35% to 40% of medulloblastomas. Significantly, C. Traenka and M. Remke contributed equally to this work. these subgroups typically lack chromosome 17 aberrations Corresponding Authors: Elke Butt, Grombuehlstr. 12, D-97080 Wuerzburg, (4, 5), which however is the most frequent cytogenetic event Germany. Phone: 49-9313-293630; Fax: 49-9318-8883174; E-mail: butt@ – klin-biochem.uni-wuerzburg.de or Stefan M. Pfister, Im Neuenheimer Feld in medulloblastoma (11, 15 17). 280, D-69120 Heidelberg, Germany. Phone: 49-6221-424593; Fax: 49- DNA copy number aberrations of chromosome 17, includ- 6221-424639; E-mail: [email protected]. ing deletion of 17p and gain of 17q, are typically found in the doi: 10.1158/0008-5472.CAN-10-0592 presence of isochromosome 17q (i17q), the hallmark cyto- ©2010 American Association for Cancer Research. genetic abnormality of high-risk medulloblastoma (4, 5, 11). www.aacrjournals.org 8003 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst October 5, 2010; DOI: 10.1158/0008-5472.CAN-10-0592 Traenka et al. However, the driver gene(s) targeted by this cytogenetic Transcriptome analysis and microarray data analysis aberration remain unidentified. Expression profiling and microarray image analysis were We previously showed in a large cohort of patients carried out as outlined in Supplementary Materials and (n = 340) that isolated gain of chromosome 17q (without con- Methods. comitant loss of 17p as observed in i17q cases) is associated with a poor prognosis, whereas isolated 17p deletion is not cDNA synthesis and quantitative real-time PCR (11). We therefore decided to pursue the biological role of Oligo-d(t) primed cDNA synthesis of 1 μg total RNA was 17q gain in medulloblastoma. When investigating 28 pairs performed by using Superscript II Reverse Transcriptase of primary and recurrent tumors, we found that 5 out of 13 (Invitrogen) as described in the protocols of the manufacturer. tumors (38%), the primaries of which were characterized by a Each cDNA sample was analyzed in triplicate by quantitative balanced chromosome 17, showed acquired gain of 17q in real-time PCR on an ABI PRISM 7700 PCR System (Applied the relapsed tumors (18). These findings suggest that gain Biosystems) using ABsolute SYBR Green ROX Mix (ABgene) of chromosome 17q is a critically important aberration for according to the instructions of the manufacturer. Gene ex- medulloblastoma progression including metastatic dissemi- pression was normalized to three endogenous housekeeping nation in a large subset of these relapsed tumors. genes (SDHA, HPRT1,andLMNB1), which were constantly Prior attempts to identify medulloblastoma oncogenes in expressed in several expression experiments comparing sub- 17q have suggested ERBB2 (19), BIRC5 (20), and PPM1D (16). sets of primary medulloblastoma samples, medulloblastoma As none of these genes were highly ranked in our screening cell lines, and control tissues. Amplification of genomic DNA approach comparing medulloblastomas with 17q gain was excluded by intron-spanning primers and adequate test against 17q balanced tumors, we hypothesized that additional PCRs. Relative gene expression levels were calculated as candidate oncogenes in 17q should be considered. described by Pfaffl (27) with the adaptation of three used In the present study, we identified LASP1 as one of the most housekeeping genes. Primer sequences are available in differentially expressed and functionally relevant genes on 17q Supplementary Table S1. when comparing tumors with and without 17q copy number gains. The LIM and SH3 domain protein LASP1 (previously Fluorescence in situ hybridization named MLN50) was initially identified from a cDNA library Interphase fluorescence in situ hybridization analysis for of breast cancer metastases (21). LASP1 mRNA is detected chromosome 17 was performed on a medulloblastoma tissue ubiquitously at low basal levels in all normal human tissues microarray containing 207 tumor samples and 10 samples of (22), but the protein is highly overexpressed in more than nontumoral cerebellar tissues as controls (11). A commercial 55% of metastatic human breast cancer (23) and ovarian can- probe set delineating the loci of interest was used: 17p13.3/ cer (24). In a recent case control study, LASP1 expression in LIS1 (spectrum orange) and 17q21/RARA (spectrum green; mammary carcinomas correlated significantly with tumor size Vysis). Evaluation criteria and cutoffs were applied as and nodal positivity (25). The genomic locus of LASP1 at 17q12 described (11). is targeted by copy number gain or amplification in 20% to 30% of human breast cancers (26). Silencing of LASP1 by Immunohistochemistry RNA interference in various cell lines resulted in a strong A primary antibody to LASP1 (28) was applied at a concen- inhibition of cell migration and proliferation, with cell cycle tration of 10 μg/mL. Evaluation of immunostaining was per- arrest in G2-M phase (23, 24). These observations imply
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