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Molecular Medicine Partnership Unit

The MMPU is a joint venture between the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory (EMBL).

Microbiota Drug Metabolism and Cancer Therapy

Michael Zimmermann, Matthias Ebert and Tianzuo Zhan

Our research interest

Anti-cancer drugs often show pronounced interpersonal variation in drug response, as well as dose- and treatment-limiting adverse effects. Accumulating evidence suggests that the intestinal microbiome and its capacity to metabolize drugs play an important role for these interpersonal differences. Therefore, the gut microbiota could serve as a biomarker and target to optimize cancer therapy and alleviate adverse effects.

Our research collaboration combines expertise in clinical and translational oncology (Ebert, Zhan) with cutting-edge technologies for experimental microbiome studies (Zimmermann) to unravel the contribution of the gut microbiome to clinical responses to anti-cancer therapy.

Background

The human gut microbiota plays a vital role in human health and disease, by catabolizing food components and contributing to host metabolism. Recently, the gut microbiota was shown to actively metabolize therapeutic drugs, thereby affecting their availability and efficiency. Interpersonal variations in drug response and adverse-effects are a major challenge to personalized oncology. Currently, only few biomarkers are available that can predict therapy outcome for the majority of anti-neoplastic drug. The contribution of the gut microbiota to metabolism of anti-cancer drugs and their subsequent effects on therapy response in humans are poorly understood. 

Goals

Our interdisciplinary collaboration will establish a novel pipeline to systematically quantify the impact of gut microbial metabolism of anti-cancer compounds on drug response and adverse effects. This will pave the ground to establish microbiome-encoded predictors of therapy response and toxicity, and uncover functional links between gut drug metabolism and tumor biology that may be therapeutically exploited.

Our current and future goals are:

  • to systematically characterize the capacity of gut microbes to metabolize anti-cancer drugs of clinical relevance
  • link microbiota drug metabolism to the efficiency and adverse effects of anti-cancer drug therapies in patients
  • mechanistically connect microbiota drug interactions to specific tumor phenotypes at the molecular level using a combination of microbiota and organoid culturing approaches.
Selected publications

Ebert group:

Unveiling the culprit: the fusobacterium lineage that populates colorectal cancer.
Betge J, Ebert MP.
Signal Transduct Target Ther. 2024 May 8;9(1):122. doi: 10.1038/s41392-024-01844-x.PMID: 38719840

Engineering the gut microbiome
Bai X, Huang Z, Duraj-Thatte AM, Ebert MP, Zhang F, Burgermeister E, Liu X, Scott BM, Li G, Zuo T.
Nat Rev Bioeng 2023. doi.org/10.1038/s44222-023-00072-2

Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trial
Ebert MP, Meindl-Beinker N, Gutting T, Maenz M, Betge J, Schulte N, Zhan T, Weidner P, Burgermeister E, Hofheinz R, Vogel A, Angermeier S, Bolling C, de Wit M, Jakobs R, Karthaus M,  Stocker G, Thuss-Patience P, Leidig T, Gaiser T, Kather JN, Haertel N.
Lancet Healthy Longev 2022;3:e417–27. doi: 10.1016/S2666-7568(22)00116-7

The drug-induced phenotypic landscape of colorectal cancer organoids
Betge J, Rindtorff N, Sauer J, Rauscher B, Dingert C, Gaitantzi H, Herweck F, Srour-Mhanna K, Miersch T, Valentini E, Boonekamp KE, Hauber V, Gutting T, Frank L, Belle S, Gaiser T, Buchholz I, Jesenofsky R, Härtel N, Zhan T, Fischer B, Breitkopf-Heinlein K, Burgermeister E, Ebert MP*, Boutros M*.
Nat Commun 2022;13:3135. doi: 10.1038/s41467-022-30722-9
(*shared senior author)

CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients
Hirth M, Gandla J, Höper C, Gaida MM, Agarwal N, Simonetti M, Demir A, Xie Y, Weiss C, Michalski CW, Hackert T, Ebert MP, Kuner R.
Gastroenterology 2020;159:665-681. doi: 10.1053/j.gastro.2020.04.037

Zhan group

Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors
Bamberg LV, Heigwer F, Wandmacher AM, Singh A, Betge J, Rindtorff N, Werner J, Josten J, Skabkina OV, Hinsenkamp I, Erdmann G, Röcken C, Ebert MP, Burgermeister E, Zhan T+, Boutros M+.
Int J Cancer 2022;151:1586–1601. doi:10.1002/ijc.34155

Multi‐omics integration identifies a selective vulnerability of colorectal cancer subtypes to YM155
Zhan T+, Faehling V+, Rauscher B+, Betge J, Ebert MP, Boutros M.
Int J Cancer 2021;148:1948–1963. doi:10.1002/ijc.33393

Detection of mutational patterns in cell free DNA (cfDNA) of colorectal cancer by custom amplicon sequencing
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.
Mol Oncol 2019;13:1669–1683. doi:10.1002/1878-0261.12539

MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
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.
Nat Commun 2019;10:2197. doi:10.1038/s41467-019-09898-0

Zimmermann group

Mapping human microbiome drug metabolism by gut bacteria and their genes
Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL.
Nature 2019; 27;570(7762):462–7.

Separating host and microbiome contributions to drug pharmacokinetics and toxicity
Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL.
Science 2019; 8;363(6427). (doi:10.1126/science.aat9931)

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