Research Group Translational Gastrointestinal Oncology – Therapy resistance of colorectal cancer (Prof. Dr. Tianzuo Zhan)

German Version

Research areas

Colorectal cancer is one of the most common types of cancer worldwide. Many colorectal cancers are diagnosed at an advanced stage, with poor prognosis despite the introduction of new targeted therapies. A major problem in the management of colorectal cancer is the development of resistance to chemotherapy and targeted therapies during the treatment.  The underlying molecular mechanisms are poorly understood.

The aim of the research group is to elucidate the biological processes that lead to therapy resistance and to develop new strategies to overcome this resistance. We work very closely with research groups at the German Cancer Research Center (DKFZ) and the European Molecular Biology Laboratory (EMBL). Our focus is on the following areas:

1. The role of Wnt signaling in therapy resistance

The Wnt signaling pathway is crucial for both embryonic development and carcinogenesis of many cancers. In particular, the formation and maintenance of normal and cancer stem cells in the intestine depend on the Wnt signaling pathway. We are interested in how the Wnt pathway can influence response to chemotherapy and targeted therapies. We have shown that specific inhibitors of the Ras-MAPK pathway activate Wnt signaling in colon cancer models. This adaptive response could be a cause of resistance to targeted therapies. Our goal is to decipher the molecular interactions between the Ras and Wnt signaling pathways and, based on this, to develop new therapeutic approaches.

Relevant publications:

Zhan T*, Ambrosi G*, Wandmacher AM*, Rauscher B, Betge J, Rindtorff N, Häussler R, Hinsenkamp I, Bamberg L, Hessling B, Müller-Decker K, Erdmann G, Burgermeister E, Ebert MP, Boutros M. MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer. Nat Commun 2019; 10: 2197.

Zhan T*, Rindtorff N*, Boutros M. Wnt signaling in cancer. Oncogene 2017; 36: 1461–1473.

2. Systematic identification of novel mechanisms of therapy resistance

Chemotherapy, targeted therapies and radiation are essential pillars in the treatment of colorectal cancer. The molecular mechanisms that lead to resistance to these therapies are complex and often unknown. To identify novel causes of therapy resistance, we collaborate with research partners at DKFZ to perform pooled CRISPR/Cas9 or large-scale drug screens, with the aim to identify new candidate genes whose silencing can enhance or reduce the antineoplastic effect of different treatment modalities. We use patient-derived organoids as an important model system for the translational validation of our candidates.

Relevant publications:

Bamberg, L.V., Heigwer, F., Wandmacher A.M., Singh A., Betge J., Rindtorff N., Werner J., Josten J., Skabkina O.V., Hinsenkamp I., Erdmann G., Röcken C., Ebert M.P., Burgermeister E., Zhan T.*, and Boutros M.*. Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors. Int. J. Cancer. 2022; 151(9):1586-1601.

Zhan, T*., V. Faehling*, B. Rauscher*, J. Betge, M.P. Ebert, and M. Boutros. Multi‐omics integration identifies a selective vulnerability of colorectal cancer subtypes to YM155. Int. J. Cancer 2021; 148: 1948-1963.

3. The impact of the gut microbiome on cancer therapies (Molecular Medicine Partnership Unit – Microbiota Drug Metabolism and Cancer Therapy)

Interindividual differences in therapy response and adverse are major challenges for cancer medicine. Experimental and preclinical studies have shown that the gut microbiome can metabolize a variety of drugs. The extent to which this bacterial drug metabolism occurs in patients and influences cancer therapy is poorly known. As part of the Molecular Medicine Partnership Unit (MMPU), we work with Matthias Ebert at UMM and Michael Zimmermann at EMBL to unlock the potential of the gut microbiome for personalized oncology. We are conducting joint clinical studies with microbiome analyses of cancer patients to identify new biomarkers for therapeutic response. To this end, we have established a large biobank for fecal and blood samples from patients with gastrointestinal cancer. In addition, we are experimentally characterizing the effect of bacterial metabolites on therapeutic response in colon cancer models.

Microbiota Drug Metabolism and Cancer Therapy – Molecular Medicine Partnership Unit (embl.org)

4. Clinical and translational validation of precision oncology

Targeted therapies are an important component of gastrointestinal oncology. The spectrum of these therapies has expanded significantly in recent years. To better understand their effectiveness, we document the clinical course of patients with gastrointestinal cancers who are treated with targeted therapies. In addition, we systematically collect plasma samples from these patients for molecular analysis, with the aim to identify new biomarkers for therapy response or resistance. 

Relevant publications:

Dreikhausen, L., Klupsch, A., Wiest, I., Xiao, Q., Schulte, N., Betge, J., Boch, T., Brochhausen, C., Gaiser, T., Hofheinz, R.D., Ebert, M.P., Zhan T. Clinical impact of panel gene sequencing on therapy of advanced cancers of the digestive system: a retrospective, single center study. BMC Cancer 2024; 24(1):526.

Herrmann S*, Zhan T*, Betge J*, Rauscher B*, Belle S, Gutting T, Schulte N, Jesenofsky R, Haertel N, Gaiser T, Hofheinz RD, Ebert MP, Boutros M. Detection of mutational patterns in cell free DNA (cfDNA) of colorectal cancer by custom amplicon sequencing. Mol Oncol 2019; 13: 1669–1683.