Neurologie und Poliklinik Teil der Neurologischen Klinik
Neurologie und Poliklinik Teil der Neurologischen Klinik
Kliniken &… Kliniken Neurologische… Neurologie und… Forschung Neurooncology Lower Grade…

NEUROONCOLOGY OF LOWER GRADE GLIOMAS

OVERVIEW

Research of the Max-Eder Research Group Neuro-oncology of Lower Grade Gliomas (set-up in October 2016 at NCT) focuses on the role of IDH1 mutations in gliomagenesis. IDH mutations are found in 80% of adult grade II/III gliomas and the presence of the mutation establishes DNA hypermethylation, an aberrant chromatin state and a block in differentiation. Yet, the precise molecular mechanisms by which IDH mutations contribute to gliomagenesis are not yet fully understood.

We integrate next-generation sequencing with cell biology and biochemistry to address the following major research efforts in our lab:

  1. Determine intratumoral heterogeneity of gliomas at the single cell level
  2. Characterize oncogenic cooperativity between IDH1 mutations and concurrent secondary alterations
  3. Develop a strategy to identify druggable molecular vulnerabilities in IDH1 mutant gliomas to establish therapeutic benefit.
  4. Generate in vivo models of IDH mutant lower grade gliomas to understand interaction of tumor cells with their microenvironment in the mouse brain.
  5. Investigate aberrant transcriptional circuitries in malignant gliomas

We hope to understand the impact of an aberrant epigenome driven by mutant IDH1 on cellular states of glioma precursor cells and define secondary mutations that cooperate with mutant IDH1. Our ultimate goal is to develop new therapeutic approaches for gliomas that may contribute significantly to the treatment of this frequently lethal cancer.

Team

Arbeitsgruppenleiterin

Wiss. Mitarbeiter/-innen

Alumnae und Alumni

  • Ruslan Al-Ali
  • Franziska Heilmann
  • Stefanie Jung
  • Omer Kilic
  • Jongwhi Park
  • Julianna Varga

SELECTED PUBLICATIONS

  • Narayanan A, Blanco-Carmona E, Demirdizen E, Sun X, Herold-Mende C, Schlesner M, Turcan S. Nuclei Isolation from Fresh Frozen Brain Tumors for Single-Nucleus RNA-seq and ATAC-seq. J Vis Exp. 2020 Aug 25;(162). doi: 10.3791/61542. PMID: 32925882.
  • Park JW, Sahm F, Steffl B, Arrillaga-Romany I, Cahill D, Monje M, Herold- Mende C, Wick W, Turcan Ş. TERT and DNMT1 expression predict sensitivity to decitabine in gliomas. Neuro Oncol. 2020 Sep 3:noaa207. doi: 10.1093/neuonc/noaa207. Epub ahead of print. PMID: 32882013.
  • Al-Ali R, Bauer K, Park JW, Al Abdulla R, Fermi V, von Deimling A, Herold- Mende C, Mallm JP, Herrmann C, Wick W, Turcan Ş. Single-nucleus chromatin accessibility reveals intratumoral epigenetic heterogeneity in IDH1 mutant gliomas. Acta Neuropathol Commun. 2019 Dec 5;7(1):201. doi: 10.1186/s40478-019-0851-y. PMID: 31806013; PMCID: PMC6896263.
  • Turcan S, Makarov V, Taranda J, Wang Y, Fabius AWM, Wu W, Zheng Y, El-Amine N, Haddock S, Nanjangud G, LeKaye HC, Brennan C, Cross J, Huse JT, Kelleher NL, Osten P, Thompson CB, Chan TA. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nat Genet. 2018 Jan;50(1):62-72. doi: 10.1038/s41588-017-0001-z. Epub 2017 Nov 27. PMID: 29180699; PMCID: PMC5769471.
  • Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW,Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A,Morris LG, Huse JT, Mellinghoff IK, Chan TA. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012 Feb 15;483(7390):479-83. doi: 10.1038/nature10866. PMID: 22343889; PMCID: PMC3351699.
  • Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay SB, Sorensen EA, Turcan Ş, Bakırcığlu M, Carrión-Grant G, Murray PB, Clark VE, Ercan-Sencicek AG, Knight J, Sencar L, Altınok S, Kaulen LD, Gülez B, Timmer M, Schramm J, Mishra-Gorur K, Henegariu O, Moliterno J, Louvi A, Chan TA, Tannheimer SL, Pamir MN, Vortmeyer AO, Bilguvar K, Yasuno K, Günel M. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nat Genet. 2016 Jan;48(1):59-66
  • Turcan S*, Fabius AWM*, Borodovsky A, Pedraza A, Brennan C, Huse J, Viale A, Riggins GJ, and Chan TA. Efficient Induction of Differentiation and Growth Inhibition in IDH1 Mutant Glioma Cells by the DNMT Inhibitor Decitabine. Oncotarget. 2013 Oct;4(10):1729-36
  • Rohle D*, Popovici-Muller J*, Palaskas N*, Turcan S,* Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013 May 3;340(6132):626-30
  • Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O’Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012 Feb 15;483(7390):474-8
  • Turcan S*, Rohle D*, Goenka A*, Walsh L, Fang F, Yilmaz E, Campos C, Fabius AWM, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LGT, Huse JT, Mellinghoff I, Chan TA. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012 Feb 15;483(7390):479-83

CAREER OPPORTUNITIES

Postdoctoral fellows:

We are looking for talented postdoctoral fellows with an interest in cancer epigenetics and translational cancer research. We use next-generation sequencing, molecular biology, biochemistry and mouse models to study the role of somatic alterations in chromatin reorganization and epigenetic regulation in gliomas. If interested, please send your CV, a summary of accomplishments/research interests and contact information for three references to Sevin Turcan.

PhD students:

If you’re a student interested in studying glioma epigenetics, please send us an E-Mail.