Neural Crest Gene Regulatory Networks Underlying Normal Meningeal Development and Onset of Meningioma
Institution:
California Institute of Technology
Researcher(s):
Ayyappa Raja Desingu Rajan, PhD
Grant Type:
Young Investigator Grants
Type of Childhood Cancer:
General Pediatric Cancer
Project Description:
Pediatric meningiomas can occur sporadically or in the context of neurofibromatosis type-2, but also are the predominant cancers induced by radiation during cranial radiotherapy (CrRT). Meningiomas arise due to gene inactivation/mutations in the primordial meningeal cells, which originate during embryonic development from either neural crest or mesodermal cells. During normal development, the neural crest is characterized by its multipotency, migratory behavior, and broad ability to differentiate into derivatives as diverse as the peripheral nervous system, craniofacial skeleton, and portions of the cardiovascular system. Extensive evidence suggests that neural crest-derived tumors express gene signatures characteristic of early neural crest cells and often re-express developmental gene regulatory network programs. Here we propose to test the hypothesis that pediatric meningiomas recapitulate early aspects of the developmental neural crest gene regulatory network (GRN) during initiation of tumor formation. To this end, I propose to perform genomic and epigenomic analysis of meningeal development compared with meningioma tumor progression using single-cell RNA-seq and ATAC-seq across different developmental and tumor onset time points. These datasets will help reveal transcriptional and epigenetic heterogeneities during meningeal development and help identify the cell type of origin during tumorigenesis.