Characterizing the Blood Brain Barrier of Pediatric Brain Tumors
Mentor: Dr. Mark Souweidane
The brain tumor microenvironment (TME) is unique compared to other tumors because it is isolated behind the blood-brain-barrier (BBB). Under physiologic conditions, the BBB functions to protect the brain from infection and injury. Brain tumors commonly disturb the BBB. Angiogenesis is one of the hallmarks of cancer, and tumors both co-opt existing vasculature (angiogenesis) and circulating cells (vasculogenesis). As in many other pathologic processes, these vessels tend to be abnormal, though they retain some central nervous system characteristics. This leads to disturbances in the BBB, which may be referred to as the blood-tumor-barrier (BTB). However, disturbances tend to be very heterogeneous within the tumor. Interestingly, there are also tumors, including diffuse intrinsic pontine glioma (DIPG), where the BBB often does not enhance using Magnetic Resonance Imaging (MRI) with Gadolinium (Gd), suggesting that it has not been disturbed, which may relate to its location, as the brainstem has been postulated to have a more restrictive BBB. There is also a difference among medulloblastomas where the WNT subtype is more likely to have a disrupted BBB than the other types, which may relate to the particular molecular characteristics of these tumors. However, a clear consensus regarding the integrity of the BBB has not been established across human pediatric brain tumors.
In order to investigate this, we will perform a retrospective chart review across cohorts at Weill Cornell Medicine and Memorial Sloan Kettering to assess the BBB status of various pediatric brain tumor types, grades, and anatomic locations based on enhancement with Gd on MRI at diagnosis, as well as operative reports for intra-operative hemorrhage, which has been associated with abnormal blood vessels and BBB disruption. If available, we will also complement this with analysis of an independent cohort from the Children’s Brain Tumor Tissue Consortium. In parallel, she will also analyze the BBB in paraffin-embedded patient samples, including extent of protein leakage, cell relationships, patterns of vessels, and markers of the BBB including CD31, ZO-1, Claudin-5, Mfsd2a, Pdgfrβ, and JAM-A. We will also determine whether there is any relationship between BBB status and survival. Finally, she will use available genomic data to explore possible mechanisms of disruption. We expect that these experiments will lead to a conclusive determination of the status of the BBB in pediatric brain tumors as well as identification of associated molecular characteristics. This will provide a basis for further research into mechanisms of BBB penetration for rapid clinical translation.
