Neural Crest Gene Regulatory Networks Underlying Normal Meningeal Development and Onset of Meningioma
California Institute of Technology
Ayyappa Raja Desingu Rajan, PhD
Young Investigator Grants
Type of Childhood Cancer:
General Pediatric Cancer
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.
Nervous system tumors (NSTs) contribute to almost 30% of childhood cancers. In the majority of cases, surgical resection is life-threatening and Cranial radiotherapy (CrRT) is the preferred treatment. However, CrRT increases the risk of secondary neoplasms and the childhood cancer survivors frequently develop aggressive meningiomas that carry NF2 gene mutation signatures. Pediatric meningiomas exhibit unique pathological, clinical, and molecular features as compared to their adult counterparts. Most notably, pediatric meningiomas behave as atypical or malignant (WHO grade II &III) and represent around 20-25% of the cases. Additionally, pediatric meningiomas have been reported to recur more frequently when compared to adult meningiomas.
Evidence suggests that pediatric meningiomas share several features with the neural crest subtype of meningioma. In particular, the neural crest subtype of meningioma is most common in males, has poor prognosis, atypical/malignant tumor signatures and strong NF2 driver gene association. The aim of this proposal is to understand the contribution of neural crest cells and underlying gene regulatory mechanisms in pediatric meningiomas. Parsing the gene regulatory network (GRN) controlling neural crest specification and differentiation into meningeal cells during normal development is poised to provide helpful information about tumorigenesis and cancer metastasis leading to meningioma. Moreover, determining the GRN circuitry underlying meningeal development and comparing this to that active at the onset of meningioma holds the promise of yielding insights into new therapeutic genetic targets.