Funding tool: Basic research projects
Project-ID: LS16-021
Project start: 01. August 2017
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 279.000,00

Brief summary:

Metastatic spread causes 90% of all tumor related fatalities and thus represents the greatest challenge for cancer patient survival. Tumor cells need to become motile and cross vascular barriers for metastatic spread. How these processes are controlled is not yet fully understood. The laboratory of Dr. Daria Siekhaus has identified a novel transporter, CG8602, required for Drosophila macrophages to invasively migrate into the tissues of the embryonic germband. Data from the Siekhaus lab point towards a role for CG8602 in regulating the glycosylation and stability of proteins that limit tissue entry. CG8602 appears necessary for the increased level of T antigen present on the surface of macrophages invading the tissue of the germband. Intriguingly, increased levels of T antigen have been found in metastatic cancer and antibodies against T antigen can reduce metastasis. This raised our interest in translating our findings into vertebrates, and Dr. Siekhaus recruited a post-doctoral fellow, Dr. Marko Roblek, with extensive experience in studying metastasis in mice back to Austria from Switzerland. This fellowship will help pay for his salary and material costs and thus enable him to conduct the work that will form the foundation for establishing his own independent lab. The mammalian ortholog of the CG8602 transporter, called MFSD1, is highly conserved, and belongs to the solute carrier superfamily (SLC). Yet its functions remain unknown due to a lack of prior studies. We seek to examine the role of MFSD1 in tumor cells during mouse metastatic initiation, We also will examine whether and how MFSD1 is involved in regulating protein glycosylation, protein stability, and how these potential changes affect the regulation of invasive tumor migration. By analyzing the function of MFSD1 and its interaction partners we aim to uncover the mechanism from aberrant glycosylation to the invasive migration phenotype observed during metastatic spread of tumors. This will include analysis of cell surface proteins, signaling cascades, and transcriptional regulation of cell migration. To test the relevance of these findings for the clinic, we are partnering with Dr. Wiesholzer and Dr. Kitzwoegerer at the Clinical Division for Internal Medicine, KLU University St Poelten. By analyzing resected tumor tissue from patients we will determine whether the level or localization of MFSD1 can be correlated with disease prognosis. We are eager to transfer findings from Drosophila to the vertebrate system in the context of metastasis research. Our prior data leads us to believe that this will lead to the description of an evolutionarily conserved mechanism that regulates invasive migration regulation from fly to vertebrates. This work can lay the ground work for understanding the basic biology of a novel vertebrate gene involved in regulating invasion and metastasis, and thus for the eventual development of a new therapeutic target and diagnostic biomarker for the clinic.

Keywords:
Cell migration, Glycosylation