Cancer Metabolism | Signaling

Our group is working on basic research and translational aspects of glioblastoma brain tumor pathomechanisms.
The main focus lies in elucidating the oncogenic role of the metabolic enzyme branched-chain amino acid transaminase 1 (BCAT1) in cancer. We initially discovered BCAT1 as an oncogene in glioblastoma brain tumors, followed by breast cancers and myeloid leukemias. We found that BCAT1 regulates DNA methylation and hypoxia-gene expression and interacts with the tumor microenvironment through its metabolites. In collaboration with academic and commercial partners, we have developed BCAT1 small-molecule inhibitors. We are continuing characterizing BCAT1-dependent oncogenic regulation, identifying additional signaling mechanisms and therapeutic targets.

Furthermore, we are performing translational studies of candidate genes that we identified in an integrated multi-omics analysis of glioblastoma patient tumors.
Specifically, we are investigating the role of the epigenetic modifier SOX10 in therapy-induced subtype reprogramming and tumor progression. In this project, we are characterizing tumor-stroma interactions in SOX10 knockdown and control tumors by single-cell sequencing of syngraft mouse tumors. Identified mechanisms and potential inhibitors are tested by genetic manipulation and pharmacologic inhibition in stem-cell-derived syngraft mouse models, and human PDX models.
In addition, we have identified combination therapies targeting the transcription factor GLI1 processes it regulates. We have identified recurrent GLI1-fusion genes in glioblastoma and soft-tissue sarcoma associated with GLI1 overexpression and the activation of DNA-repair pathways. We will performing pre-clinical tests using cerebral organoid and mouse xenograft models.

• Wu Y, Fletcher M, Gu Z, ..., Herrmann C, Radlwimmer B. (2020) Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype. Nat Commun 11, 6434.

• Raffel S, Falcone M, Kneisel N, ..., Radlwimmer B*, Trumpp A*. (2017) BCAT1 restricts alphaKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551, 384-388. (* = shared senior authorship)

• Kretzmer H, Bernhart S, ..., Lichter P, Siebert R, Hoffmann S, Radlwimmer B. (2015) DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat Genet 47, 1316-1325.

• Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, Pleier SV, ..., Reifenberger G, Lichter P, Radlwimmer B. (2013) BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 19, 901-908.