The cysteine protease cathepsin S mediates niche activation through effects of the tumor cells and stroma cells of the micronevironment in brain metastases: approaches

• Applicant: Professorin Lisa Sevenich, Ph.D.
• Subject Area: Cell Biology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 216995176

Metastasis remains the single most lethal aspect of cancer. Despite advances in the treatment of local cancers, few therapies succeed at combating disseminated disease, particularly for brain metastases. While the tumor microenvironment has emerged as a major regulator of cancer progression in other organ sites, our knowledge of the brain metastatic microenvironment is currently very limited. Therefore I aim to analyze tumor-stroma interactions in brain metastasis to potentially identify novel therapeutic targets. Preliminary data suggest that the cysteine protease cathepsin S (CatS) is a key mediator of experimentally induced brain metastasis in a xenograft mouse model. CatS shows a particularly intriguing expression pattern, with high expression in tumor cells early in metastatic development, which is downregulated at the later stages concomitant with an increase in stromal CatS expression. Interestingly, only the combined depletion of both tumor and stromal derived CatS significantly reduced brain metastasis incidence. Thus, the aim of my project is to identify mechanisms by which CatS regulates distinct steps of brain colonization. In addition to the model I used for the preliminary experiments, I seek to establish other brain metastasis mouse models to verify the generalizability of my findings. Moreover, I will test the efficacy of a pharmacological inhibition of CatS on brain metastasis in pre-clinical trials. In order to determine a possible correlation with patient prognosis, I will analyze the cell-type specific expression of CatS in pathology samples. I strongly believe that the findings on the role of CatS in brain metastasis will be beneficial for understanding tumor-stroma interaction and provide a strong scientific foundation for the future development of novel, effective therapeutic strategies for this devastating disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Johanna Joyce, Ph.D.