Research Projects

Brain metastasis, especially from aggressive cancers like breast cancer, is a significant clinical challenge and remains a leading cause of cancer-related mortality. The blood-brain barrier (BBB), a specialized endothelial interface, plays a critical role in maintaining brain homeostasis by limiting the entry of circulating cells and molecules. However, during metastatic progression, cancer cells hijack the BBB's regulatory mechanisms, leading to increased permeability and facilitating the invasion of metastatic cells. The precise molecular mechanisms underlying this endothelial dysfunction and BBB breakdown remain poorly understood. Endothelial cells (ECs) are central to maintaining BBB integrity through tight regulation of vascular barrier function. Mechanosensitive transcription factors KLF2 and KLF4 are crucial for BBB integrity, promoting anti-inflammatory and barrier-protective effects under normal laminar shear stress. In contrast, disturbed flow conditions suppress KLF2/4, leading to EC dysfunction. ESM1, a proteoglycan upregulated during inflammation and disturbed flow, is linked to increased vascular permeability and a pro-metastatic environment. Our preliminary analysis reveal significant downregulation of KLF2/4 and marked upregulation of ESM1 in ECs from metastatic brain, suggesting a novel KLF2/4-ESM1 axis driving endothelial dysfunction and BBB disruption. Understanding this mechanism could uncover early events in brain metastasis and identify new therapeutic targets. This study aims to elucidate how tumor-altered fluid dynamics and secreted factors reprogram ECs via the KLF2/4-ESM1 axis, leading to BBB breakdown and the formation of a pro-metastatic niche. We hypothesize that the loss of KLF2/4 signaling, triggered by disturbed shear stress and tumor-derived factors, drives upregulation of ESM1, resulting in endothelial activation, increased BBB permeability, and facilitation of brain metastasis. We will investigate the KLF2/4-ESM1 axis in BBB disruption using in vitro and in vivo models, identify tumor-derived modulators of this pathway through proteomics and transcriptomics, and assess the impact of altered mechanosensing on BBB integrity using shear stress models and in vivo imaging. This study will uncover a novel mechanosensitive pathway involving the KLF2/4-ESM1 axis in endothelial reprogramming during brain metastasis. By linking alterations in mechanosensing and EC metabolism to BBB disruption, we aim to provide a deeper understanding of brain metastasis. The findings could reveal novel therapeutic targets aimed at restoring BBB function, preventing metastatic cell entry, and ultimately improving clinical outcomes for patients with brain metastasis.