Die Bedeutung von Tumor- und Stromazellen in der Hirnmetastasierung und Therapieresistenz des Mammakarzinoms.
Zusammenfassung der Projektergebnisse
Both brain metastases and gliomas confer a devastating prognosis for patients. The influence of nonmalignant, stromal cells of the tumor microenvironment is being increasingly appreciated as an important effector that shapes the survival, growth and invasion of the malignant cells but also alters therapeutic response and has profound effects on therapeutic efficacy. Through the use of clinical samples from patients I was able to generate a comprehensive cellular and molecular map of the tumor microenvironment in brain malignancies. This was achieved through the use of different techniques that dissected these tumors at different levels of granularity. This approach revealed stark differences in the recruitment of cells from the periphery – while brain metastases show a complex enrichment of immune cells of both myeloid and lymphocytic origin this is much less diverse in glioblastoma. However, in both diseases a significant influx of bone marrow derived macrophages occurs. Analysis of the tumor microenvironment’s cell types through RNAseq unraveled not only shared but also cell-type and disease-specific education patterns. As an example, in the case of tumor associated microglia and macrophages both cell types show an enrichment of genes and pathways that modulate inflammation but also have adopt unique responses that are governed by distinct transcriptional networks. Combining these population-based analyses with bulk protein data further elucidated the composition of brain malignancies. It also facilitates the identification of the cellular origin of proteins and thus distinguishes tumor cell-derived factors from microenvironmental sources. Ultimately, analyses at the single cell level demonstrated a surprising heterogeneity for some of these signaling cascades and points toward possible crosstalk between subsets of tumor cells and microenvironmental populations. Ultimately, this work has led the foundation for a model of brain malignancies that consists of single- or multicellular signaling hubs that are not only highly interconnected to cells of their own type but also exhibit a connections to other cell types. These cellular units might orchestrate the microenvironment’s response and pose potential targets for pharmacological inhibition of brain metastases and high grade gliomas.
Projektbezogene Publikationen (Auswahl)
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Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015 Apr;25(4)
Klemm F, Jocye JA
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Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies. Cell Rep. 2016 Nov22;17(9)
Bowman RL, Klemm F, Akkari L, Pyonteck SM, Sevenich L, Quail DF, Dhara S, Simpson K, Gardner EE, Iacobuzio-Donahue CA, Brennan CW, Tabar V, Gutin PH, Joyce JA
