Endoplasmic reticulum stress (ER stress) is a cellular stress response. Three transmembrane ER proteins function as ER stress sensors and elicit the unfolded protein response (UPR) as adaptive cellular mechanism to mitigate the ER stress and promote cell survival. We are specifically focusing on the regulation of the Inositol-requiring enzyme 1α (IRE1α) pathway of UPR as a potential facilitator for brain colonization of metastatic cells and their survival in the perivascular niche. Specific inhibition of the IRE1α RNAse activity results in distinct proteomic changes in human breast cancer brain metastasizing cells that may influence their brain metastatic competency.

Brain metastasis requires the specific interaction of cancer cells with the endothelium at brain capillaries and post-capillary venules that finally result in the cancer cells crossing of the blood-brain-barrier. Different from other organs, microvessels in the brain have higher than 50% coverage by perivascular pericytes, a cell type with high phenotypic plasticity and stem cell capability. We aim to better understand the cell-cell communication between metastasizing cancer cells and these resident cells of the in the perivascular niche to identify key adaptive mechanisms that are required for survival and early metastatic growth.

We perform proteomic profiling and kinome arrays of patient-derived brain metastatic cells to discover prominent survival pathways that can be targeted by drugs. In collaboration with the NIH we test novel brain penetrable drugs for their effectiveness in preventing brain colonization or delaying metastatic growth in our mouse model for brain metastasis.