Tep1 Regulates Yki Activity in Neural Stem Cells in Drosophila Glioma Model.

Karishma Gangwani,Madhuri Kango-Singh,Kirti Snigdha

doi:10.3389/fcell.2020.00306

Karishma Gangwani, Madhuri Kango-Singh + Show 1 more

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https://doi.org/10.3389/fcell.2020.00306

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Abstract

Glioblastoma Multiforme (GBM) is the most common form of malignant brain tumor with poor prognosis. Amplification of Epidermal Growth Factor Receptor (EGFR), and mutations leading to activation of Phosphatidyl-Inositol-3 Kinase (PI3K) pathway are commonly associated with GBM. Using a previously published Drosophila glioma model generated by coactivation of PI3K and EGFR pathways [by downregulation of Pten and overexpression of oncogenic Ras] in glial cells, we showed that the Drosophila Tep1 gene (ortholog of human CD109) regulates Yki (the Drosophila ortholog of human YAP/TAZ) via an evolutionarily conserved mechanism. Oncogenic signaling by the YAP/TAZ pathway occurs in cells that acquire CD109 expression in response to the inflammatory environment induced by radiation in clinically relevant models. Further, downregulation of Tep1 caused a reduction in Yki activity and reduced glioma growth. A key function of Yki in larval CNS is stem cell renewal and formation of neuroblasts. Other reports suggest different upstream regulators of Yki activity in the optic lobe versus the central brain regions of the larval CNS. We hypothesized that Tep1 interacts with the Hippo pathway effector Yki to regulate neuroblast numbers. We tested if Tep1 acts through Yki to affect glioma growth, and if in normal cells Tep1 affects neuroblast number and proliferation. Our data suggests that Tep1 affects Yki mediated stem cell renewal in glioma, as reduction of Tep significantly decreases the number of neuroblasts in glioma. Thus, we identify Tep1-Yki interaction in the larval CNS that plays a key role in glioma growth and progression.

Highlights

Glioblastoma multiforme (GBM) is a primary malignant adult brain tumor with extremely poor prognosis (Ostrom et al, 2017)
We previously showed that loss of the Drosophila homolog of CD109, Thioester containing protein 1 (Tep1) in glioma cells substantially reduced Yki levels and activity, and attenuated gliomagenesis in-vivo (Minata et al, 2019)
The size of the developing central nervous system (CNS) depends on the proliferative potential of NSCs, due to the finite progeny produced by this cell type

Summary

Introduction

Glioblastoma multiforme (GBM) is a primary malignant adult brain tumor with extremely poor prognosis (Ostrom et al, 2017) Current therapies such as surgery and chemo- and/or radiotherapy only provide palliative care resulting in median GBM patient survival of about 14–15 months (Ghinda et al, 2016). Amplification of EGFR is the most frequent alteration, followed by activating mutations in PI3K [PI3KCA] and loss of PTEN [phosphatidyl-inositol 3-phosphate (PIP3) lipid phosphatase] (Gao et al, 2000). These alterations result in constitutive activation of PI3K (Read et al, 2009). The genes and proteins required for neural development perform identical functions resulting in the presence of analogous cell types in fly and human central nervous system (CNS) (Karim et al, 1996; Voas and Rebay, 2004; Freeman and Doherty, 2006; Furnari et al, 2007; Wilson et al, 2010; Homem et al, 2015)

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