PD Dr. Frank Westermann
Group leader "Neuroblastoma"
German Cancer Research Center
Div. Neuroblastoma Genomics / B087
Im Neuenheimer Feld 280
D- 69120 Heidelberg
Neuroblastomas are a very heterogeneous group of tumors that almost exclusively occur in children. They develop in the first years of life from immature cells of the peripheral nervous system and in some cases regress by themselves. However, they can also grow extremely aggressively and then become life-threatening.
In order to be able to adapt the intensity of the therapy as closely as possible to the individual characteristics of the tumor, our work group "Neuroblastomas", which corresponds to the DKFZ division "Neuroblastoma Genomics" (headed by PD Dr. Frank Westermann), deals with risk assessment by means of molecular markers. Also, our aim is to derive individualized therapeutic approaches in order to provide the patient with the best possible treatment.
We work on molecular risk stratification and customized therapies for particularly aggressive forms of neuroblastoma. For this we need an accurate understanding of the development, progression and therapy resistance of neuroblastomas. Here, a special role is played by a malfunction of the transcription factor MYCN, which is regularly observed in particularly aggressive tumors. MYCN is involved in almost all aspects of tumor formation: unrestrained proliferation, inhibition of differentiation, adaptation of cellular energy metabolism, vascularization, infiltration / metastasis, and genomic instability.
The specific aim of our work is to identify the causative genetic changes in neuroblastoma and to characterize the divergent clinical progression employing comprehensive molecular genetic characterization (project NB genome / epigenome / transcriptome) of the different neuroblastoma subtypes (e.g. by means of global gene expression, DNA methylation analysis and high-throughput sequencing). The project “NB Enhancer Translocations” deals with the detailed characterization of chromosomal rearrangements in neuroblastoma cells, in which regulative genomic regions (so-called "super-enhancers") translocate into the context of oncogenes and thereby activate them. Here, histone modification analyses (ChIP-seq) and 3D chromatin context analyses (e.g. circular chromatin conformation capturing, 4C) are used. In the “NB Achilles” project, we use functional high-throughput analyses (siRNA / shRNA screening procedures) to systematically detect targetable factors in neuroblastoma cells. We are particularly looking for weak spots associated with specific changes in cancer cells (e.g. MYCN amplification, TERT rearrangements, ATRX deletions, chromosome 1p loss) with one focus being dependencies mediated by these changes. We expect that some of these vulnerabilities could be targets for new cancer medicines. In the project “MYC-NET” we use systems biology approaches to investigate the role of the oncoprotein MYCN in cell cycle, apoptosis, and senescence of cancer cells and normal cells. Another focus of our research group is the identification of genetic risk factors for the expression of chromosomal breaks, which can lead to the development of amplifications and other DNA damage in neuronal tumors (“Fragilome” project).
Gartlgruber M, Sharma AK, Quintero A, Dreidax D, Selina J, Park YG, Gogolin S, Meder J, Doncevic D, Saary P, Toprak UH, Afanasyeva E, Koster J, Versteeg R, Grünewald TGP, Jones DTW, Pfister SM, Henrich KO, van Nes J, Herrmann C, Westermann F. 2020. 'Super enhancers define regulatory subtypes and cell identity in neuroblastoma'. Nature Cancer (https://rdcu.be/cbOJ7).
Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A, Bartenhagen C, Walter E, Gecht J, Kerschke L, Volland R, Menon R, Heuckmann JM, Gartlgruber M, Hartlieb S, Henrich KO, Okonechnikov K, Altmüller J, Nürnberg P, Lefever S, de Wilde B, Sand F, Ikram F, Rosswog C, Fischer J, Theissen J, Hertwig F, Singhi AD, Simon T, Vogel W, Perner S, Krug B, Schmidt M, Rahmann S, Achter V, Lang U, Vokuhl C, Ortmann M, Büttner R, Eggert A, Speleman F, O'Sullivan RJ, Thomas RK, Berthold F, Vandesompele J, Schramm A, Westermann F, Schulte JH, Peifer M, Fischer M. 2018. A mechanistic classification of clinical phenotypes in neuroblastoma. Science, 362: 1165-70.
Jones DTW, Banito A, Grunewald TGP, Haber M, Jager n, Kool M, Milde T, Molenaar JJ, Nabbi A, Pugh TJ, Schleiermacher G, Smith MA, Westermann F, Pfister SM. 'Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours', 2019. Nat Rev Cancer, 19: 420-38.
Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M, Menon R, Kramer A, Roncaioli JL, Sand F, Heuckmann JM, Ikram F, Schmidt R, Ackermann S, Engesser A, Kahlert Y, Vogel W, Altmuller J, Nurnberg P, Thierry-Mieg J, Thierry-Mieg D, Mariappan A, Heynck S, Mariotti E, Henrich KO, Gloeckner C, Bosco G, Leuschner I, Schweiger MR, Savelyeva L, Watkins SC, Shao C, Bell E, Hofer T, Achter V, Lang U, Theissen J, Volland R, Saadati M, Eggert A, de Wilde B, Berthold F, Peng Z, Zhao C, Shi L, Ortmann M, Buttner R, Perner S, Hero B, Schramm A, Schulte JH, Herrmann C, O'Sullivan RJ, Westermann F, Thomas RK, Fischer M. 2015. 'Telomerase activation by genomic rearrangements in high-risk neuroblastoma', Nature, 526: 700-4