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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
Year Awarded: 
2021
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.

Project Goal:

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.

Project Update 2024:

Meningiomas are typically benign tumors that arise from the meninges of the central nervous system because of mutations in the gene NF2 or as a result of cranial radiotherapy treatments in pediatric cancer patients. To treat meningiomas effectively, it is critical to understand the cell type of origin for the tumors. I used the animal model zebrafish to study meninges development and meningeal tumor formation. I have established cell-type specific zebrafish transgenic lines expressing fluorescent proteins in meningeal progenitor cells derived from the neural crest and mesoderm origin stem cells. These lines will aid in visualizing meningeal progenitor cells and help us track them across development. Additionally, I have generated a zebrafish tumor model that develops meningioma using conditional gene editing techniques. I can pinpoint the cell type of origin for meningeal tumors by combining cell visualization via transgenic line, gene editing to generate tumors, and state of-the-art imaging and sequencing technologies.

Final Project Update 2025:

I have created transgenic lines that label the meningeal progenitors and have characterised their development and transcriptional signatures. Furthermore, I have produced a zebrafish tumor model that induces meningioma by applying conditional gene editing techniques. These hyperproliferating meningeal fibroblasts demonstrate transcriptional signatures reminiscent of muscle cells indicating cell type transformation. Additionally, I have established that NF2 along with other pediatric meningioma associated genes regulate cellular proliferation and spatial distribution in a combinatorial fashion. In conclusion, by integrating cell visualization using transgenic lines, tumor generation through gene editing, and advanced imaging and sequencing technologies, I can accurately identify the cell type from which meningeal tumors originate.     
 

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