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Investigating Anti-Cancer Signalling...

Pokrajac, Nenad.

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Investigating Anti-Cancer Signalling in the Meninges During Medulloblastoma Development = = Istrazivanje antikancerogenih signala u meningama tijekom razvoja meduloblastome.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Investigating Anti-Cancer Signalling in the Meninges During Medulloblastoma Development =/
Reminder of title:	Istrazivanje antikancerogenih signala u meningama tijekom razvoja meduloblastome.
Author:	Pokrajac, Nenad.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
Description:	214 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-05, Section: B.
Contained By:	Dissertations Abstracts International85-05B.
Subject:	Neurosciences. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30569927
ISBN:	9798380832861

Investigating Anti-Cancer Signalling in the Meninges During Medulloblastoma Development = = Istrazivanje antikancerogenih signala u meningama tijekom razvoja meduloblastome.
Pokrajac, Nenad.

Investigating Anti-Cancer Signalling in the Meninges During Medulloblastoma Development =Istrazivanje antikancerogenih signala u meningama tijekom razvoja meduloblastome. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 214 p.

Source: Dissertations Abstracts International, Volume: 85-05, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2023.

.

Medulloblastoma (MB) is the most common solid malignant paediatric tumour. Sonic hedgehog signalling, which drives cerebellar development, also potentiates the formation of MB tumours (Shh-MB) from granule neuron progenitors (GNPs) in the external granular layer (EGL). Like many cancers, Shh-MB tumours accrue mutations in tumour drivers and suppressors to promote malignancy, which are necessary but not sufficient to the formation of tumours. Tumourigenesis is augmented by sustained activation of microenvironmental pathways that promote proliferation, but analysis of these pathways is hindered by the complexity of the tumour and its microenvironment. Deeper insight into the mechanism of Shh-MB has the potential to uncover novel pathways to target this tumor. In brain tumours, interactions between the meningeal microenvironment and tumourigenesis are understudied. During cerebellar development, canonical Wnt signalling mediated by Norrin/Frizzled4 (Fzd4) activation in meningeal endothelial cells is a potent inhibitor of preneoplasia and tumour progression in mouse models of Shh-MB. As a bridge between the meningeal microenvironment and cerebellar tumourigenesis, the discovery of Norrin regulated factors in cerebellar tumourigenesis will aid in the creation of new therapeutic strategies in Shh-MB. In this thesis, I developed a tractable method using 3DISCO tissue clearing with light sheet fluorescence microscopy (LSFM) to characterize cerebellar development and to identify and quantify preneoplastic changes associated with disruption Norrin/Frizzled4 signalling. I developed models for the quantification of PNL formation in Ptch+/− mice and EGL hyperplasia in Neurod2-SmoA1+/− mice, which led to the discovery that the anti-tumour effect of Norrin/Fzd4 signalling is restricted to the posterior region of the cerebellum and is characterized by defective GNP migration away from the EGL. Single cell transcriptome profiling and deep phenotyping of the meninges revealed that Norrin/Fzd4 signalling maintains the activation of meningeal macrophages (mMΦs), characterized by Lyve1 and CXCL4 expression, during the critical period for preneoplasia. mMΦ depletion during this critical period phenocopies the enhanced preneoplasia and tumourigenesis caused by Norrin loss. Moreover, CXCL4 mediates the anti-tumourigenic effect of mMΦs, as it antagonizes CXCL12/CXCR4 signaling in GNPs to reduce cell cycle progression and promote migration away from the pre-tumour niche. These findings prove that mMΦs are key mediators of chemokine-regulated anti-cancer cross talk between the stroma and pre-tumour cells in the control of Shh-MB initiation.

ISBN: 9798380832861Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Chemokine signalling

Investigating Anti-Cancer Signalling in the Meninges During Medulloblastoma Development = = Istrazivanje antikancerogenih signala u meningama tijekom razvoja meduloblastome.
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502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2023.
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