Baumann, Zora. Immuno-metabolic effects of a ketogenic diet on mammary cancer metastases. 2024, Doctoral Thesis, University of Basel, Faculty of Science.
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Abstract
Breast cancer is the most frequent cancer in women, with roughly 2.6 million new annual diagnoses worldwide. Metastases arise in distant tissues such as the lung, liver, and bones, representing the fatal hallmark of the disease and accounting for up to 90% of cancer-related deaths.
Cell metabolism is crucial for cell survival, and a modified metabolism is one of the main hallmarks of cancer. Notably, the metabolism of primary tumors and metastases is often distinct. Diets are a powerful non-invasive tool that can modulate systemic host metabolism and the immune system. Indeed, a ketogenic diet combined with neoadjuvant chemotherapy has been shown to shrink primary breast tumors, but its effect on metastases remains unknown.
In my PhD studies, I aimed to investigate the effects of a ketogenic diet on mammary cancer metastasis. This objective was divided into two interconnected projects.
In the first project we surprisingly found that while a ketogenic diet significantly reduces primary mammary tumors, it increases lung metastases. Additionally, the ketogenic diet broadly altered the organ-specific immune and systemic endocrine landscape. Notably, the diet-induced increase in metastatic burden depended on the presence of tissue-resident alveolar macrophages. These macrophages were more abundant in the lungs of ketogenic- diet-fed mice, and their ablation reduced lung metastases. Furthermore, we discovered that the ketogenic diet enhances stress hormone levels, which create immunosuppressive alveolar macrophages by lowering anti-inflammatory cytokine secretion and phagocytic capacity. These cellular changes are likely mediated by the activated glucocorticoids receptor repressing NF-kB signaling. Our study highlights the need for caution when patients with breast cancer follow a ketogenic diet.
In the second project, I developed an optimized 27-color full-spectrum flow cytometry panel to deeply characterize the metastatic immune microenvironment at a single-cell level. This advanced panel combines lineage markers with numerous inhibitory and activating receptors, providing researchers with a comprehensive overview of the immune system in the lung. Full-spectrum flow cytometry offers significant advantages, but its high sensitivity requires precise fine-tuning of antibody combinations for optimal data unmixing. We discovered that tissue-resident alveolar macrophages exhibit high autofluorescence across all channels, complicating data unmixing. By dissecting lung autofluorescent signatures, we improved data unmixing in conjunction with a well-designed antibody combination. Our panel sets a foundation for researchers interested in lung immunology, extending beyond oncology research. It is a powerful tool ready for direct application in various experiments or adaptable to specific research needs.
Cell metabolism is crucial for cell survival, and a modified metabolism is one of the main hallmarks of cancer. Notably, the metabolism of primary tumors and metastases is often distinct. Diets are a powerful non-invasive tool that can modulate systemic host metabolism and the immune system. Indeed, a ketogenic diet combined with neoadjuvant chemotherapy has been shown to shrink primary breast tumors, but its effect on metastases remains unknown.
In my PhD studies, I aimed to investigate the effects of a ketogenic diet on mammary cancer metastasis. This objective was divided into two interconnected projects.
In the first project we surprisingly found that while a ketogenic diet significantly reduces primary mammary tumors, it increases lung metastases. Additionally, the ketogenic diet broadly altered the organ-specific immune and systemic endocrine landscape. Notably, the diet-induced increase in metastatic burden depended on the presence of tissue-resident alveolar macrophages. These macrophages were more abundant in the lungs of ketogenic- diet-fed mice, and their ablation reduced lung metastases. Furthermore, we discovered that the ketogenic diet enhances stress hormone levels, which create immunosuppressive alveolar macrophages by lowering anti-inflammatory cytokine secretion and phagocytic capacity. These cellular changes are likely mediated by the activated glucocorticoids receptor repressing NF-kB signaling. Our study highlights the need for caution when patients with breast cancer follow a ketogenic diet.
In the second project, I developed an optimized 27-color full-spectrum flow cytometry panel to deeply characterize the metastatic immune microenvironment at a single-cell level. This advanced panel combines lineage markers with numerous inhibitory and activating receptors, providing researchers with a comprehensive overview of the immune system in the lung. Full-spectrum flow cytometry offers significant advantages, but its high sensitivity requires precise fine-tuning of antibody combinations for optimal data unmixing. We discovered that tissue-resident alveolar macrophages exhibit high autofluorescence across all channels, complicating data unmixing. By dissecting lung autofluorescent signatures, we improved data unmixing in conjunction with a well-designed antibody combination. Our panel sets a foundation for researchers interested in lung immunology, extending beyond oncology research. It is a powerful tool ready for direct application in various experiments or adaptable to specific research needs.
Advisors: | Bentires-Alj, Mohamed |
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Committee Members: | Schär, Primo Leo and Benarafa, Charaf |
Faculties and Departments: | 03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Tumor Heterogeneity Metastasis and Resistance (Bentires-Alj) 03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Molecular Genetics (Schär) |
UniBasel Contributors: | Bentires-Alj, Mohamed and Schär, Primo Leo |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 15526 |
Thesis status: | Complete |
Number of Pages: | 157 |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 28 Nov 2024 13:00 |
Deposited On: | 14 Nov 2024 14:57 |
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