Project Details
Projekt
Tumor and Stromal Contributions in Breast Cancer Brain Metastases and Therapeutic Resistance.
Applicant
Dr. Florian Klemm
Subject Area
Hematology, Oncology
Term
from 2014 to 2016
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 261943804
Metastasis to distant sites, including the brain, remains the single most lethal aspect of breast cancer. Despite important advances in the treatment of localized breast cancer, few therapies succeed at combating disseminated disease. Unfortunately, this is a particularly dire problem for patients with brain metastases, as there are currently no effective treatment options. Clearly, novel perspectives are required to identify and mechanistically understand the critical regulators of breast to brain metastasis, with the long-term goal of identifying effective therapeutic strategies. Recently, the Joyce Lab has identified the protease cathepsin S (CTSS) as a novel mediator of breast-to-brain metastasis. However, the potential roles of other upregulated cathepsin family members (e.g. CTSB, CTSC and CTSL) in metastatic seeding and/or outgrowth have not been investigated to date. Preliminary results suggest that CTSC and CTSL may constitute novel proteolytic components in breast cancer that play a role during breast-to-brain metastasis. Both CTSC and CTSL are upregulated in tumor cells during brain metastasis and correlate with reduced overall survival and brain metastasis-free survival in patients. Additionally, within the stromal compartment, the expression of the protease inhibitor TIMP1 is elevated in tumor-associated astrocytes during brain metastatic outgrowth. Interestingly, TIMP1 exhibits multifaceted roles not only as a tumor promotor but also as a mediator of therapeutic resistance. Thus, I will investigate the role of CTSC, CTSL and TIMP1 in mediating breast-to-brain metastasis, tumor-stroma-interactions and metastatic phenotypes (i.e. extravasation, invasion and colonization). Furthermore, I will determine whether the tumor microenvironment contributes to the establishment of a chemoresistant niche via TIMP1 in breast-to-brain metastasis. Finally, to validate my experimental findings in a clinical setting I will study brain metastases tissue samples from breast cancer patients. I strongly believe that the findings on the role of CTSC, CTSL and TIMP1 will contribute to the understanding of in brain metastasis, tumor-stroma interactions and therapeutic resistance and will ultimately provide a sound scientific foundation for the future development of novel, effective therapeutic strategies.
DFG Programme
Research Fellowships
International Connection
USA
