Wunderlich, Thomas - A 11
The crosstalk between marginal zone B cells and female hormonal state in the development of benign liver cancer
Prof. Dr. Thomas Wunderlich
Department for Endocrinology, Diabetology and Preventive Medicine | Max Planck Institute for Metabolism Research
CMMC - PI - A 11
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Department for Endocrinology, Diabetology and Preventive Medicine | Max Planck Institute for Metabolism Research
Gleueler Str. 50
50931 Cologne
Introduction
Females are more prone to develop autoimmune diseases than men at least in part due to their hormonal state. In pregnancy, female sex hormones regulate immunity to tolerate the embryo. Here, estrogen affects marginal zone (MZ) B cell functions that reside exclusively in the MZ of the spleen and are the first line of defence against infections comprising innate polyreactive IgM responses, inflammatory cytokine expression as well as antigen presentation to T cells. Several reports have demonstrated that uncontrolled MZ B cell functions in females cause autoimmunity via dysregulated estrogen signaling. On the other hand, approx. half of sexually active women take contraceptives to prevent unwanted pregnancy thereby not only interfering with the estrous cycle but also affecting MZ B cell functions. Although liver cancer is much more prominent in males than in females, 4 out of 105 women on long term contraceptives develop benign liver tumors of hepatic adenoma or focal nodular hyperplasia types - however the underlying mechanisms are completely unknown.
We have made the surprising observation that transgenic MZ B cells with compound overactive AKT and Notch1 signaling cause spontaneous liver cancer exclusively in female mice with 100% penetrance. Though the transgenic MZ B cells are still retained in the spleen, they somehow guide T cells and neutrophils to the liver where they cause liver damage and cancer. In the next funding period, we aim at investigating how MZ B cells cause liver tumors in females to set the ground for future therapeutic intervention.
Clinical Relevance
Prolonged contraceptive intake can cause benign liver tumors in women, however, the molecular mechanisms behind remain completely unresolved. Any insights into the nature of such liver tumors might help to develop novel therapeutic approaches to combat this complication. Given our finding that MZ B cells in the spleen induce spontaneous cancer in the liver might open new avenues to treat the disease at extrahepatic sites. Thus, studying the basic principles of contraceptive-induced liver tumors will provide novel projections in therapeutic interventions.
Approach
- Dietary interference in spontaneous female liver cancer
- Antigen presenting functions of MZ B cells in female liver cancer
- Determining the natural mechanism how compound AKT and Notch1 signaling in MZ B cells induces female liver cancer
Lab Website
For more information, please check the Wunderlich Research Site.
Publications generated during 1/2023-12/2025 with CMMC affiliation
2024 (up to June)
- Henschke S, Nolte H, Magoley J, Kleele T, Brandt C, Hausen AC, Wunderlich CM, Bauder CA, Aschauer P, Manley S,Langer T, Wunderlich FT, and Bruning JC (2024). Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver. Science384, 438-446. doi:10.1126/science.adk1005.
- Vossen C, Schmidt P, Wunderlich CM, Mittenbuhler MJ, Tapken C, Wienand P, Mirabella PN, Cabot L, Schumacher AL, Folz-Donahue K, Kukat C, Voigt I, Bruning JC, Fenselau H, and Wunderlich FT (2024). An Approach to Intersectionally Target Mature Enteroendocrine Cells in the Small Intestine of Mice. Cells13. doi:10.3390/cells13010102.
2023
- Nagao H, Cai W, Brandao BB, Wewer Albrechtsen NJ, Steger M, Gattu AK, Pan H, Dreyfuss JM, Wunderlich FT, Mann M, and Kahn CR (2023). Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling. J Clin Invest 133. doi:10.1172/JCI161472.