Cancers of the brain tend to be among the most fatal, due to their rapid rates of growth and challenges in transporting therapeutics across the blood-brain barrier (BBB), one of the tightest vascular barriers in humans. High-grade glioma, the most common type of primary brain cancer, has one of the worst prognoses of all tumors with a five-year survival rate of ~2.4%. In addition, an estimated 20% of all cancer patients develop brain metastases. The lack of physiologically relevant in vitro human BBB models as well as the challenges in translating results from animal experiments to the clinic have significantly hindered progress in improving patient outcomes. There is thus a critical need to develop physiological brain-on-a-chip models that allow for high spatio-temporal resolution imaging to understand the mechanisms of tumor progression at the brain and develop new therapeutic strategies for brain cancers.

Here, we address this need with the design of an in vitro microvascular model of the human BBB in a microfluidic chip to evaluate cellular and molecular interactions between cancer cells and brain stromal cells. The self-assembled BBB vascular networks are generated entirely with human cells, using induced pluripotent stem cell-derived endothelial cells, primary brain pericytes, and astrocytes. The addition of brain stromal cells improved barrier function and decreased vessel permeabilities to values comparable to in vivo measurements. Astrocytes were identified to play a central role in tumor transmigration through their secretion of CCL2. This chemokine is internalized by CCR2-expressing cancer cells and promotes their extravasation via both chemotaxis and chemokinesis. Expanding upon this assay, we incorporated a high-grade glioma tumor spheroid in the in vitro brain vasculature to study brain-stroma interactions and novel therapeutic approaches for primary brain tumors. Layered nanoparticles targeting LRP1 exhibited improved trafficking at the BBB via transcytosis near glioma tumors. Importantly, encapsulating chemotherapy cisplatin in the nanoparticles resulted in targeted apoptosis in the tumor area compared to free cisplatin, which damaged the surrounding healthy BBB vessels. This in vitro brain microvascular model with relevant BBB properties recapitulates the early steps of the metastatic cascade at the brain and enables the in-depth investigation of tumor progression at the brain to accelerate the development of targeted therapies.

Cynthia Hajal obtained her BA in Economics from Columbia College and BS in Mechanical Engineering from Columbia Engineering in 2016. During this time, she worked in the lab of Dr. James Hone as an undergraduate research assistant. Following her undergraduate studies, she moved to MIT where she completed her PhD in Mechanical Engineering in Dr. Roger Kamm's Mechanobiology lab. Her work focused on the design of in vitro brain-on-a-chip systems to study cancer progression and novel therapeutic approaches to target brain tumors. She defended her PhD in 2020 and is now a postdoctoral research fellow in the lab of Dr. Keith Ligon at Harvard Medical School and the Dana-Farber Cancer Institute. In her current role, she is investigating the mechanisms of resistance to chemotherapies in brain tumors. Today, she will be presenting her work on engineered microvascular brain-on-a-chip models to study tumor progression.