Identification of Neuroprotective Mechanisms and Cellular Interactions in Pediatric Brain Tumors
Jeremy Amen
Mentors: Dr. Robert Suter and Dr. Nagi Ayad, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center.
Date/Time: August 23rd, 2024 at 3:40pm.
Abstract: Pediatric brain cancer such as Sonic Hedgehog medulloblastoma (SHH MB) present significant challenges, particularly in patient survivorship and post-chemotherapeutic quality of life. Current treatments often illicit undesirable effects on neurodevelopmental pathways, leading to long-term detriment in patient outcomes.These long-term deficits in quality of life are correlated with younger ages at diagnosis, thus the identification of neuroprotective therapeutics to use in combination with current standards of care is essential. To identify druggable neuroprotective mechanisms, we integrated single-cell RNA sequencing data from early normal human embryonal brain (Eze et al., 2021) with that of patient SHH medulloblastoma tumor samples (Riemondy et al., 2021) to leverage pharmacotranscriptomic approaches developed in the lab. In silico drug connectivity analysis was performed using the tool ISOSCELES to predict the response of both tumor and normal cell types to the chemotherapeutic agent Vincristine, using a transcriptional consensus signature (TCS) derived from the NIH Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 dataset. Using these results, we employed the R package CellChat to infer and compare cell-cell communication networks between normal cell types grouped by predicted sensitivity to vincristine, with the aim of uncovering pathways that support neuronal survival and function. In silico drug connectivity analysis generated both sensitive and resistant cell populations across different cell types, revealing comparable connectivity between SHH tumor samples and neuronal cells. Notably, radial glia cells and Intermediate Progenitor Cells (IPCs) exhibited increased predicted sensitivity to vincristine treatment. Using differential expression analysis, we dissected our predictions to find contrasting genes within the vincristine TCS having specific reversal of tumor cell signatures or normal neurodevelopmental cell signatures. Differential expression predicted genes of the synaptic vesicle cycle pathway as a potential target of neuroprotection. CellChat analysis highlighted differences in communication and interaction between sensitive and resistant populations, with the former showing increased intercellular communication. Key signaling, including the Semaphorins and EPHB pathways, which play crucial roles in brain development and function, were predicted to be lost with vincristine treatment. Also, IPC interactions, which were exclusive to sensitive populations, emerged as a potential target for neuroprotection. Our findings reveal critical insights into the cellular interactions and pathways that underlie neurotoxicity in the context of the standard of care for pediatric brain cancers and lay the groundwork for the prioritization of neuroprotective candidate drugs to use in combination with effective treatment. The identification of sensitive populations and their specific interactions offers a promising avenue for developing targeted therapies that protect normal neuronal function while undergoing additional chemotherapeutic treatment.