Research Program “Exploitation of Oncogenic Mechanisms” (EOM)

The primary goal of the program Exploitation of Oncogenic Mechanisms (EOM) is to gain a better understanding of the errors and combinations of errors within the complex cross-linked cellular and molecular mechanisms that can result in cancer. By using newest molecular biological, biochemical and bioinformatics technologies as well as in vivo models the scientists of the program investigate which genes and proteins are active and which are turned off during tumor development, and how these molecular differentiations influence the course of the disease and the course of the therapy.

© Madhavicmu / WikiMediaCommons

© Madhavicmu / WikiMediaCommons

Gained knowledge on oncogenic mechanisms, is exploited to define therapeutic targets, therapeutic strategies an biomarkers. The investigations are focused on questions about intracellular communication and regulation mechanisms, the role and regulation of cancer stem cells, communication of tumor cells with their environment (tumor microenvironment), and so-called epigenetic mechanisms of gene regulation.
The program focuses on evaluating mechanistic hypotheses of cancer biology, with the broader aim of obtaining preclinical evidence that it is promising to therapeutically target these mechanisms. By discovering novel mechanisms and by dissecting cellular and molecular pathways, including those responsible for therapy resistance, the program provides the basis for biology-driven diagnostic or therapeutic strategies, including druggable targets. It can thus be considered as the mechanistic arm uncovering the Achilles heels of cancer and cancer stem cells.

Furthermore, results of clinical studies within DKTK will be reverse-translated into molecular studies within the EOM Program with the aim of characterizing their functions.

Highlight Achievements

  • The observation of a long non-coding RNA (TARID) that acts as an address label to direct DNA-demethylating protein complexes, including GADD45A, TET and TDG to target promoter sites (Arab et al., Mol Cell 2014.).
  • The description of the molecular, cellular and epigenetic regulation of the hierarchy in hematopoiesis (Cabezas-Wallscheid et al., Cell Stem Cell 2014).
  • The identification in breast cancer patients of circulating CD44 + MET + CD47 + metastasis stem cells with the potential to re-initiate metastasis formation in PDX models (Baccelli et al., Nature Biotechnol 2013).
  • The demonstration that MYC controls the entry and exit of stem cells from dormancy. This work showed that proliferation and metabolic activity can be separated from stem cell identity in the self-renewal process. This work has important implications for the generation and survial of domant metastasis stem cells (Scognamiglio et al., and Trumpp, Cell 2016).
  • Establishment of a PDX platform for pancreatic cancers, and the identification of a twomarker set to stratify three PDAC subtypes. In addition, CYP3A5-dependent primary and secondary resistance mechanism against tyrosine kinase inhibitors and paclitaxel were uncovered (Noll et al., and Weichert, Trumpp, Sprick, Nature Med 2016).
  • Elucidated that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting the IL-6R/STAT3/miR-34a feedback loop (Rokavec et al., J Clin Invest 2014).
  • Identification of IκB kinase α (IKKα) as a central regulator of a tumoricidal
    microenvironment during intestinal carcinogenesis and as a promising target for CRC therapy (Göktuna et al., Cell Rep 2014).
  • A collaborative DKTK effort in which high-throughput data and systems biology analyses indentified novel facets of the clinically applied B-Raf or MEK inhibitors, which promote the cellular adhesion and differentiation of CRC cells (Herr et al., Cancer Res 2015).
  • The identification in senescent lymphoma cells of proteotoxic stress caused by their secretory phenotype and accompanied by an increase in the unfolded protein response, endoplasmic reticulum stress and autophagy (Dörr et al., Nature 2013).

Coordinators

Prof Dr Florian Greten
Georg-Speyer-Haus, Frankfurt/Mainz