28B. Advancing DMG-midbrain organoids to model crosstalk between DMG and the human brain microenvironment

There is currently no effective treatment for Diffuse Midline Glioma (DMG), a highly aggressive pediatric brain tumor with a devastating prognosis. Clinicians and researchers face a pleiotropy of hurdles that make this disease very challenging to treat. A key issue is the lack of accessible experimental systems that accurately model these challenges, such as the unique location of the tumor, its diffuse manifestation and an almost intact blood brain barrier (BBB), all heavily complicating successful treatment. By introducing DMG driver mutations in newly established human organoids with midbrain identity, we have recently developed a novel human DMG model. Importantly, this model recapitulates critical features of the disease, such as invasion into the healthy brain tissue. Indeed, the resulting DMG tumors highly resemble primary patient material, outperforming commonly applied patient-derived xenografts (PDXs) and cell lines.

In this project, we will apply bioengineering approaches to further advance these DMG-midbrain organoids into a more complex model for understanding and manipulating DMG crosstalk with the brain microenvironment. Through expertise in the latest 3D bioprinting technology and synthetic matrices, we will introduce vascularization. Not only will this allow for nutrient supplementation via the vascular route, it will also enable modeling of the largely intact BBB that forms a critical obstacle for effective treatment delivery. In addition, we will increase cellular complexity by introducing immune cells into the DMG-organoid model, allowing to model tumor-immune interplay and the impact of a potentially immune suppressive environment on T cell therapy, a main focus of DMG therapy development. To achieve these goals, we are looking for a PhD candidate with a strong background in bioengineering that can develop and apply the latest bioprinting and engineering technologies to lift our DMG-midbrain organoids to the next level for modeling microenvironmental crosstalk.

Necessary skills for this position:

• Background in biofabrication