As societies age, cancer is becoming one of the most important medical problems. My goal is to identify genes and processes upon which cancer cells are particularly dependent. My group uses genome-wide methods to better understand the biology of tumours and genetic screens to detect novel therapeutic targets in cancer cells.
A hallmark of tumours is deregulated signalling pathways, which significantly change the transcriptional profile of malignant cells. MYC family proteins play a prominent role as transcription factors in this oncogenic reprogramming. Nearly all human tumours express significantly more MYC protein than healthy tissue, and mouse models show a clear correlation between MYC activity and cancer development. Yet, until recently, MYC has not been seen as a promising therapeutic target due to difficulty inhibiting transcription factors with small molecules and MYC’s crucial function in normal cells. We hypothesized that a better mechanistic understanding of MYC could allow identification of novel strategies to inhibit MYC-mediated oncogenic transformation. To do this, we characterized both target gene regulation by MYC and its interaction partners by a combination of next-generation-based analyses, mass spectrometry and murine tumour models and made two fundamental observations. First, my group discovered that MYC regulates different sets of genes at low (physiological) and high (oncogenic) levels, because of promoters’ varying affinity for MYC (eLife 2016, Nature 2014), offering a potential strategy to specifically target MYC´s oncogenic function. Second, we observed that MYC activates genes by recruiting transcriptional elongation factors to promoters and transferring them onto the RNA polymerase (Molecular Cell, in press). In the future, my lab will focus on elucidating the structural details of this transfer model and using these mechanistic insights to identify novel therapeutic strategies to target the oncogenic function of MYC.
Baluapuri A, Hofstetter J, Dudvarski N, Endres T, Bhandare P, Vos SM, Adhikari B Schwarz JD, Narain A, Vogt M, Wang SJ, Düster R, Jung LA, Vanselow JT, Wiegering A, Geyer M, Maric HM, Gallant P, Walz S, Schlosser A, Cramer P, Eilers M, Wolf E: MYC recruits SPT5 to RNA polymerase II to promote processive transcription elongation, Molecular Cell, published online:doi: 10.1016/j.molcel.2019.02.031
Lorenzin F, Benary U, Baluapuri A, Walz S, Jung LA, von Eyss B, Kisker C, Wolf J, Eilers M, Wolf E (2016) Different promoter affinities account for specificity in MYC-dependent gene regulation, eLife, e15161
Vo BT*, Wolf E*, Kawauchi D, Gebhardt A, Rehg JE, Finkelstein D, Walz S, Murphy BL, Youn YH, Han YG, Eilers M*, Roussel MF*(2016) The interaction of Myc with Miz1 defines medulloblastoma subgroup identity, Cancer Cell, 29, 5-16 *joined first and senior authors
Wolf E, Lin CY, Eilers M, Levens DL (2014) Taming of the beast: shaping Myc-dependent amplification. Trends in Cell Biology
Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, Rycak L, Dumay-Odelot H, Karim S, Bartkuhn M, Roels F, Wustefeld T, Fischer M, Teichmann M, Zender L, Wei C-L, Sansom O, Wolf E*, Eilers M* (2014) Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature 511: 483-487 *joined senior authors
Wolf E*, Gebhardt A*, Kawauchi D, Walz S, von Eyss B, Wagner N, Renninger C, Krohne G, Asan E, Roussel MF, Eilers M (2013) Miz1 is required to maintain autophagic flux. Nat Commun 4: 2535 *joined first authors