Glioblastoma (GBM) represents the most frequent and lethal cancer affecting the central nervous system for which no cure is currently available. The presence of Glioma Stem Cells (GSCs) has been proposed to be at the root of therapeutic failures due to their intrinsic abilities of escaping common treatments and relapsing the pathology. Thus, advances in therapeutic options may derive from the manipulation of mechanisms controlling the GSCs self-renewal, survival and functions. RE1-Silencing Transcription Factor (REST) is a master repressor of neuronal developmental programme in non-neuronal lineages, recently described as a main actor in the maintenance of the GSCs’ tumorigenic competence as its knockdown strongly impairs GSCs stemness both in vitro and in vivo. However, REST is critical for restraining neuronal cellular identity in various tissues, so that a targeted therapy to this transcriptional repressor is likely to present numerous side effects. Here, by taking advantage of a Tet-on system for the manipulation of REST expression in both human GSCs and Neural Stem Cell lines (hNSCs), we performed a transcriptomic profiling analysis in order to identify novel tumour-specific REST-regulated functions and molecular targets. Our analyses confirmed the previously reported roles of REST in neural tissues and enlightened novel REST functions in hGSCs, including the regulation of alternative hGSCs identity/state. Finally, analysis of hGSC-specific REST-regulated genes in GBM patients’ dataset revealed an inverse correlation with glioma aggressiveness, thus establishing a hGSC REST score that might provide a useful prognostic tool.

Identification of REST-Regulated Molecular Circuitries and Targets Exploitable for hGSCs-Targeted Therapies / Zasso, Jacopo. - (2018), pp. 1-187.

Identification of REST-Regulated Molecular Circuitries and Targets Exploitable for hGSCs-Targeted Therapies

Zasso, Jacopo
2018-01-01

Abstract

Glioblastoma (GBM) represents the most frequent and lethal cancer affecting the central nervous system for which no cure is currently available. The presence of Glioma Stem Cells (GSCs) has been proposed to be at the root of therapeutic failures due to their intrinsic abilities of escaping common treatments and relapsing the pathology. Thus, advances in therapeutic options may derive from the manipulation of mechanisms controlling the GSCs self-renewal, survival and functions. RE1-Silencing Transcription Factor (REST) is a master repressor of neuronal developmental programme in non-neuronal lineages, recently described as a main actor in the maintenance of the GSCs’ tumorigenic competence as its knockdown strongly impairs GSCs stemness both in vitro and in vivo. However, REST is critical for restraining neuronal cellular identity in various tissues, so that a targeted therapy to this transcriptional repressor is likely to present numerous side effects. Here, by taking advantage of a Tet-on system for the manipulation of REST expression in both human GSCs and Neural Stem Cell lines (hNSCs), we performed a transcriptomic profiling analysis in order to identify novel tumour-specific REST-regulated functions and molecular targets. Our analyses confirmed the previously reported roles of REST in neural tissues and enlightened novel REST functions in hGSCs, including the regulation of alternative hGSCs identity/state. Finally, analysis of hGSC-specific REST-regulated genes in GBM patients’ dataset revealed an inverse correlation with glioma aggressiveness, thus establishing a hGSC REST score that might provide a useful prognostic tool.
2018
XXX
2018-2019
CIBIO (29/10/12-)
Biomolecular Sciences
Conti, Luciano
no
Inglese
Settore BIO/13 - Biologia Applicata
File in questo prodotto:
File Dimensione Formato  
JZ_PhD_Thesis.pdf

Open Access dal 16/10/2020

Tipologia: Tesi di dottorato (Doctoral Thesis)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 42.64 MB
Formato Adobe PDF
42.64 MB Adobe PDF Visualizza/Apri
JZ_Disclaimer.pdf

Solo gestori archivio

Tipologia: Tesi di dottorato (Doctoral Thesis)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 106.35 kB
Formato Adobe PDF
106.35 kB Adobe PDF   Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/369006
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact