YB-1 Post-Transcriptionally Regulates PLXND1 to Mediate Metastasis in Sonic Hedgehog Medulloblastoma Open Access

Abstract

Medulloblastoma (MB) is one of the most common brain malignancies in children, accounting for nearly 10% of all pediatric brain tumors. The Sonic Hedgehog (SHH) subgroup, which accounts for 30% of MB cases, is characterized by tumor formation via perturbations in SHH signaling during early cerebellar development. Current treatment options are limited to surgical resection, craniospinal irradiation, and chemotherapy. This standard of treatment yields a ~60-70% survival rate with a high-risk of long-term detriments and reduced quality of life. A significant portion of mortalities from MB result from metastatic incidence or recurrence. Our study seeks to investigate potential molecular drivers of metastatic progression in SHH MB. Using in vitro primary mouse models and cell lines, we identify Y-box-binding protein 1 (YB-1) as a positive modulator of Plexin D1 (PLXND1) expression. Our studies suggest that YB-1 post-transcriptionally regulates PLXND1 to mediate cell migration, invasion, and tumor development. These findings point to this novel YB-1/PLXND1 signaling axis as a potentially relevant target for metastatic inhibition in SHH MB.

Table of Contents

Abstract.…………………………………………………………………………………………...............................4

Acknowledgements...……………………………………………………………………………............................6

Introduction .……………………………………………………………………………………..............................8

Materials and Methods………………………………………………………………………….............................12

Results……………………………………………………………………………………………...............................16

Discussion .………………………………………………………………………………………..............................19

Figures…………………………………………………………………………………………..................................21

Figure 1: Schematic depiction of YB-1/PLXND1-mediated metastasis.....………………............21

Figure 2: YB-1 positively modulates PLXND1 expression at the post-transcriptional level......22

Figure 3: PLXND1 is expressed in SHH MB.……………………………………….....................…….23

Figure 4: Silencing PLXND1 reduces tumor cell migration..………………………………..............24

Figure 5: Silencing PLXND1 reduces tumor cell invasion…………………………………...............25

Figure 6: PLXND1 drives select EMT marker expression…………………………………................26

References .………………………………………………………………………………………..............................27

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience Biology, Molecular Health Sciences, Oncology
Keyword	Y-box-binding protein 1 Neuro-Oncology Sonic Hedgehog Medulloblastoma Metastasis Pediatrics PLXND1
Committee Chair / Thesis Advisor	Anna M. Kenney, Emory University
Committee Members	Astrid Prinz, Emory University Sumin Kang, Emory University

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