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Studying the role of syndecans in breast cancer metastasis to the brain
Koblinski Lab - Group Photo [View Image]Dr. Koblinski' lab is studying breast cancer metastasis to the brain. Brain metastasis is a devastating, late-stage event affecting approximately 10-30% of breast cancer patients. However, it is not well understood how breast cancer cells migrate across the blood-brain barrier (BBB), invade into the brain, and colonize to for metastases. Syndecans (Sdcs) are a family of cell surface heparan sulfate proteoglycans (HSPGs) that have previously been linked to breast cancer progression and metastasis. Preliminary findings from the Koblinksi lab indicate that Sdc1 may be involved in breast cancer metastasis to the brain. Data from clinical samples in a TMA of breast cancer patients with brain metastases showed that 67% of the brain metastasis samples stained positive for Sdc1 expression. TCGA data also shows that breast cancer patients with high expression of Sdc1 have a worse prognosis compared to patients with low expression of Sdc1. In an experimental mouse model of metastasis, silencing expression of Sdc1 in MDA-231 breast cancer cells greatly reduced metastasis to the brain, with no difference in lung or bone metastases. Additionally, silencing expression of Sdc1 in MDA-231 cells resulted in a reduction in cancer cell migration across in vitro BBB model systems. Since BBB endothelial cell junctions have been reported to be disrupted in metastasis to the brain, immunofluorescence was performed to examine localization of junction proteins in the in vitro BBB model following addition of conditioned medium (CM) from MDA-231 non-silenced (NS1) control and Sdc1KD cells. Disruption in PECAM-1 localization at BBB endothelial cell junctions was observed upon addition of CM from MDA-231 NS1 cells with markedly less disruption occurring upon treatment with CM from Sdc1KD cells. These results suggest that paracrine factors secreted from MDA-231 cells may facilitate breast cancer cell migration across the BBB by affecting PECAM-1 localization on BBB endothelial cells. A cytokine array using CM from MDA-231 cells determined that Sdc1KD CM contained lower levels of IL-8 than MDA-231 NS1 cell CM. These findings were confirmed by ELISA, qRT-PCR, and multiplex analysis. Endothelial cells were then treated, using the RTCA xCELLigence in vitro BBB model system, with recombinant IL-8 and a sufficient decrease in cell index readings was observed. This suggested that IL-8 affects BBB barrier permeability. Additionally, in an experimental model of metastasis, mice injected with MDA-231 Sdc1KD cells had a less permeable BBB, measured by fluorescence of 680 dextran in the brain after IV injection using the IVIS imaging system, compared to those injected with MDA-231 NS1 cells at day 3 and day 7 after injection. Taken together, these results suggest that Sdc1 supports breast cancer invasion into the brain by altering BBB permeability through a signaling mechanism involving IL-8 and PECAM-1. Elucidating this mechanism will allow for the development of therapeutic strategies to combat breast cancer cell metastasis to the brain.
Researcher looking into the microscope [View Image]Our lab is also investigating how the brain environment might be shaped by breast cancer before the cells invade into the brain. This is a process called pre-metastatic niche formation. Cancer cells have been shown to prepare distant sites for tumor growth through extracellular vesicles, which are secreted vesicles containing proteins and nucleic acids. We are particularly interested in determining if breast cancer cell-derived extracellular vesicles can mediate changes in astrocytes, glial cells which have previously been demonstrated to play an important role in cancer cell survival and growth in the brain. Determining if breast cancer extracellular vesicles can promote brain pre-metastatic niche formation could provide more insight into how breast cancer cells can colonize an environment as unique as the brain.