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    Chair of Biochemistry and Molecular Biology

    Research

    Colorectal cancer (CRC) is the most common gastrointestinal malignancy. Currently, primary surgery and, depending on the tumor stage, additional chemotherapy is still the standard therapy. Due to the high recurrence rate vulnerabilities and prognostic markers specific for CRC need to be identified. At a molecular level, most CRCs are characterized by loss of the tumor suppressor gene APC which in turn leads to upregulation of the MYC oncoprotein. “The Cancer Genome Atlas” project has demonstrated that deregulated MYC expression is a hallmark of virtually all CRCs. Correspondingly, the hyperproliferative phenotype observed in a mouse model of intestinal tumorigenesis driven by APC loss can be reverted by simultaneous MYC deletion. Therefore, both APC and MYC are promising targets for therapeutic intervention, but none of these proteins are directly druggable so far.

    One of the downstream functions of MYC is activating the process of mRNA translation that is highly deregulated in many tumor entities including CRC. We and others could show that tumors display different dependencies on translation factors, ribosomal proteins and rRNAs:

    1. Mutations in the WNT signaling pathway lead to an increase in global protein synthesis rates.
    2. Colorectal tumors are dependent on certain translation initiation factors, e.g. eIF4A and eIF3D, to keep high MYC expression.
    3. Loss of the translation initiation factor eIF2B5 is synthetic lethal with APC mutation.
    4. CRCs show upregulation of RNA polymerase I.

    Based on these observations, our group aims at investigating and exploiting these dependencies to identify new tumor-specific therapeutic options for CRC. To do so, we make use of 2D and 3D (organoids) cell culture models as well as mouse models for colorectal tumors and colorectal liver metastases. Established techniques in our lab include next-generation sequencing and high-content screening as well as current state-of-the art methods as CRISPR/Cas9 and AID (auxin-inducible degron).

    Arbeitsgruppe Kolorektales Karzinom im ZOM