Pediatric brain tumors: molecular pathology and mechanisms
Pediatric brain tumors are the second most common group of childhood cancers. Despite aggressive therapeutic approaches, the prognosis of many children with brain tumors remains dismal. Little is known on targetable downstream pathways.
We aim to contribute to a better outcome in children with brain tumors. To this end, we are using various animal and cell culture models in order to identify genetic alterations and signaling pathways involved in tumor biology. The clinical role of identified pathways is confirmed in human tumor samples. One major focus of our lab is on atypical teratoid/rhabdoid tumors (AT/RT), highly malignant tumors affecting young children as well as other tumors associated with SWI/SNF dysfunction.
Clinical and molecular features predicting outcome in children with atypical teratoid/rhabdoid tumour (AT/RT)
Serving as central reference neuropathology resource for the European Rhabdoid Tumor Registry EU-RHAB, we are aiming at identifying clinical and molecular features predicting outcome in children with AT/RT and other tumors associated with SWI/SNF dysfunction. This project is done in close collaboration within an international framework of pediatric neuroncologists, molecular geneticists and basic scientists.
Functional role of epigenetic alterations in the biology of atypical teratoid/rhabdoid tumors (AT/RT)
The majority of AT/RT are characterized by inactivation of the SMARCB1 gene. In this project, we are aiming at identifying epigenetic alterations associated with SMARCB1 inactivation and validating their functional and clinical relevance. To this end, chromatin immunoprecipitation DNA sequencing (ChIP-Seq) data have been generated in a Drosophila melanogaster model of SMARCB1 deficiency. First results show that knockdown of snr1, the fly homologue of SMARCB1 leads to global changes in the distribution of the activating histone mark H3K27ac and binding of RNA-Pol II. Taking advantage of the fly model, we are currently examining the functional role of a large number of genes and regions affected by epigenetic alterations in human AT/RT and have already successfully identified over 200 possible candidate genes shifting the lethal phenotype encountered upon snr1 knockdown. The functional role of selected candidate genes is being explored in human rhabdoid cell lines. Of note, several genes involved in the detrimental effects of snr1 knockdown also shifted the lethal phenotype encountered upon overexpression of mutated human histone H3.3 (K27M) in our fly model. In summary, these findings will provide a better understanding of the functional role of epigenetic alterations in the biology of AT/RT, but also other pediatric brain tumors. Supported by IZKF Münster (Ha3/019/15)
Identification of targetable pathways involved in the biology of atypical teratoid/rhabdoid tumors (AT/RT)
Based on our previous results in a fly model of SMARCB1-deficiency we are also further investigating the role of identified candidate genes in the biology of AT/RT. Specifically, we are interested to learn why the function of the genes merlin, kibra and expanded is essential for the phenotype associated with knockdown of snr1, the fly homolog of SMARCB1. To this end, we are investigating signaling pathways using reporter assays and gene expression profiling in Drosophila melanogaster. The functional role of identified pathways is confirmed in human SMARCB1-deficient rhabdoid tumor cell lines. Supported by Deutsche Forschungsgemeinschaft (HA 3060/1)
Selected recent publications
- Jeibmann A, Schulz J, Eikmeier K, Johann PD, Thiel K, Tegeder I, Ambrée O, Frühwald MC, Pfister SM, Kool M, Paulus W, Hasselblatt M: SMAD dependent signaling plays a detrimental role in a fly model of SMARCB1-deficiency and the biology of atypical teratoid/rhabdoid tumors. J Neurooncol 2017;131:477-484
- Johann P, Hovestadt V, Thomas C, Jeibmann A, Hess K, Bens S, Oyen F, Hawkins C, Pierson CR, Aldape K, Kim S, Widing E, Sumerauer D, Hauser P, van Landeghem F, Ryzhova M, Korshunov A, Capper D, Jones D, Pfister SM, Schneppenheim R, Siebert R, Paulus W, Frühwald M, Kool M, Hasselblatt M: Cribriform neuroepithelial tumor (CRINET): Molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable longterm outcome. Brain Pathol 2017 27:411-418
- Hasselblatt M, Thomas C, Hovestadt V, Schrimpf D, Johann P, Bens S, Oyen F, Peetz-Dienhart S, Crede Y, Wefers A, Vogel H, Riemenschneider MJ, Antonelli M, Giangaspero F, Bernardo MC, Giannini C, Ud Din N, Perry A, Keyvani K, van Landeghem F, Sumerauer D, Hauser P, Capper D, Korshunov A, Jones DT, Pfister SM, Schneppenheim R, Siebert R, Frühwald MC, Kool M. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis. Acta Neuropathol 2016;132:149-51
- Thomas C, Sill M, Ruland V, Witten A, Hartung S, Kordes U, Jeibmann A, Beschorner R, Keyvani K, Bergmann M, Mittelbronn M, Pietsch T, Felsberg J, Monoranu CM, Varlet P, Hauser P, Olar A, Grundy R, Wolff JE, Korshunov A, Hovestadt V, von Deimling A, Pfister S, Paulus W, Capper D, Hasselblatt M: Methylation profiling of choroid plexus tumors reveals three clinically distinct subgroups. Neuro-Oncology 2016; 18:790-6
- Rivera B; Gayden T; Carrot-Zhang C; Nadaf J; Boshari T; Faury D; Zeinieh M; Blanc R; Burk DL; Fahiminiya S; Bareke E; Schüller U; Monoranu CM; Sträter R; Kerl K; Niederstadt T; Kurlemann G; Ellezam B; Michalak S; Thom M; Lockhart PJ; Leventer RJ; Ohm M; MacGregor D; Jones DTW; Karamchandani J; Greenwood CMT; Berghuis AM; Bens S; Siebert R; Zakrzewska M; Liberski PP; Zakrzewski K; Sisodiya SM; Paulus W; Albrecht S; Hasselblatt M; Jabado N; Foulkes WD, Majewski J: Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol 2016;131:847-63
- Johann P, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V, Sturm D, Hermann C, Wang MS, Korshunov A, Ryzhova M, Jones DTW, Northcott P, Groeschel S, Kratochwil F, Wittmann A, Sieber L, Oyen F, Capper D, Milde T, Witt O, Kulozik A, Ebinger M, Ruland V, Shalaby T, Mora J, Aronica E, Pietsch T, Schuller U, Schneppenheim R, Frühwald M, Lichter P, Eils R, Gajjar A, Hasselblatt M, Pfister S, Kool M: Atypical teratoid / rhabdoid tumor (ATRT) is an epigenetically heterogeneous disease with distinct subgroup specific enhancer landscapes. Cancer Cell 2016; 29(3):379-93
- Witkowski L, Carrot-Zhang J, Albrecht S, Fahiminiya S, Hamel N, Tomiak E, Grynspan D, Saloustros E, Nadaf J, Rivera B, Gilpin C, Castellsagué E, Silva-Smith R, Plourde F, Wu M, Saskin A, Arseneault M, Karabakhtsian RG, Reilly EA, Ueland FR, Margiolaki A, Pavlakis K, Castellino SM, Lamovec J, Mackay HJ, Roth LM, Ulbright TM, Bender TA, Georgoulias V, Longy M, Berchuck A, Tischkowitz M, Nagel I, Siebert R, Stewart CJ, Arseneau J, McCluggage WG, Clarke BA, Riazalhosseini Y, Hasselblatt M, Majewski J, Foulkes WD: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 2014;46:438-43
- Jeibmann A, Eikmeier K, Linge A, Kool M, Koos B, Schulz J, Albrecht S, Bartelheim K, Frühwald MC, Pfister SM, Paulus W, Hasselblatt M: Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster. Nat Commun. 2014;5:4005