Brain tumors are the leading cause of cancer-related deaths in infants, children, and adolescents. Our lab is mostly focusing on embryonal brain tumors including medulloblastoma, atypical teratoid rhabdoid tumors (ATRTs), and embryonal tumors with multilayered rosettes (ETMRs). Due to the lack of targeted therapies for these tumors, survival rates remain poor.
The primary aim of the lab is to identify novel targeted therapies for children with brain tumors that will result in improved survival rates and fewer long-term side effects. We are currently employing genome-wide CRISPR/Cas9 knockout screens in order to develop comprehensive maps of genetic dependencies for distinct forms of embryonal brain tumors. We correlate these essentialities with molecular features such as genetic alterations and global gene expression profiling in order to gain further insights into the molecular biology of these devastating tumors. Furthermore, we validate the most promising candidates in in vitro drug screens and in vivo mouse models to further evaluate their potential for clinical translation.
Resistance to anti-cancer treatments is a major obstacle to a cure for many brain tumor patients. We are therefore also interested in tumor-drug interactions, and how those relate to novel combination therapies and potential resistance mechanisms that will allow cancer cells to overcome targeted therapies.
Selected publications
Tsiami F, Lago C, Pozza N, Piccioni F, Zhao X, Lülsberg F, Root DE, Tiberi L, Kool M, Schittenhelm J, Bandopadhayay P, Segal RA, Tabatabai G, Merk DJ. Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma. Acta Neuropathol Commun. 2024 Aug 7;12(1):125. doi: 10.1186/s40478-024-01831-x. PMID: 39107797; PMCID: PMC11304869.
Merk DJ, Paul L, Tsiami F, Hohenthanner H, Kouchesfahani GM, Haeusser LA, Walter B, Brown A, Persky NS, Root DE, Tabatabai G. CRISPR-Cas9 screens reveal common essential miRNAs in human cancer cell lines. Genome Med. 2024 Jun 17;16(1):82. doi: 10.1186/s13073-024-01341-4. PMID: 38886809; PMCID: PMC11181638.
Merk DJ, Zhou P, Cohen SM, Pazyra-Murphy MF, Hwang GH, Rehm KJ, Alfaro J, Reid CM, Zhao X, Park E, Xu PX, Chan JA, Eck MJ, Nazemi KJ, Harwell CC, Segal RA (2020) The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors. Developmental Neuroscience 42:170-86
Pak E, MacKenzie EL, Zhao X, Pazyra-Murphy MF, Park PMC, Wu L, Shaw DL, Addleson EC, Cayer SS, Lopez BG, Agar NYR, Rubin LL, Qi J, Merk DJ, Segal RA (2019) A large-scale drug screen identifies selective inhibitors of class I HDACs as a potential therapeutic option for SHH medulloblastoma. Neuro-Oncology 21:1150-63
Merk DJ, Ohli J, Merk ND, Thatikonda V, Morrissy S, Schoof M, Schmid SN, Harrison L, Filser S, Ahlfeld J, Erkek S, Raithatha K, Andreska T, Weisshaar M, Launspach M, Neumann JE, Shakarami M, Plenker D, Marra MA, Li Y, Mungall AJ, Moore RA, Ma Y, Jones SJM, Lutz B, Ertl-Wagner B, Rossi A, Wagener R, Siebert R, Jung A, Eberhart CG, Lach B, Sendtner M, Pfister SM, Taylor MD, Chavez L, Kool M, Schuller U (2018) Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma. Developmental Cell 44:709-24 e6
Grammel D, Warmuth-Metz M, von Bueren AO, Kool M, Pietsch T, Kretzschmar HA, Rowitch DH, Rutkowski S, Pfister SM, Schuller U (2012) Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathologica 123:601-14
Frick A, Grammel D, Schmidt F, Pöschl J, Priller M, Pagella P, von Bueren AO, Peraud A, Tonn JC, Herms J, Rutkowski S, Kretzschmar HA, Schüller U. Proper cerebellar development requires expression of β1-integrin in Bergmann glia, but not in granule neurons. Glia. 2012 May;60(5):820-32. doi: 10.1002/glia.22314. Epub 2012 Feb 28. PMID: 22374686.
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