James HeFollow

Date of Completion

Spring 5-17-2021

Thesis Advisor(s)

Joseph LoTurco; Johann Peter Gogarten

Honors Major

Molecular and Cell Biology

Disciplines

Bioinformatics | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular and Cellular Neuroscience | Molecular Biology

Abstract

Ependymoma is a primary solid tumor of the central nervous system. Supratentorial ependymoma (ST-EPN), a subtype of ependymomas, is driven by an oncogenic fusion between the ZFTA and RELA genes in 70% of cases. We introduced this fusion into neural progenitor cells of mice embryos via in utero electroporation of a non-viral binary piggyBac transposon system containing ZFTA-RELA. From preliminary data in the LoTurco lab, inducing the expression of ZFTA-RELA into different neural progenitor cells produces tumors of varying lethality and cellular composition. To define the cellular composition and subclonal diversity of ST-EPN tumors, we used single cell RNA-sequencing to derive a transcriptomic profile of the heterogeneous cell types composing ST-EPN mouse tumors. Among the 20,000 cells sequenced, approximately two-thirds of the cells did not express the oncogene. These cells represent various types of immune cells, such as B-lymphocytes, T-cells, and macrophages; stromal cells, and different neural cell types (i.e. oligodendrocytes). Although ZFTA-RELA has been shown to activate NF-κB effector genes, there was not a ubiquitous upregulation of such genes across the cells enriched for ZFTA-RELA expression. Subclustering these tumorigenic cells revealed distinct subpopulations characterized by upregulation of non-NFκB pathways involved in cell proliferation, extracellular environment reorganization, and immune activation. We identified a list of specific markers for these cellular conditions to better characterize the processes underlying ST-EPN aggressiveness and immunological responses.

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