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Tor Vergata: The MYC‐interfering polypeptide, Omomyc, impairs the carcinogenic potential of human glioblastoma stemlike cells (GSCs)

8/3/2017

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 Cancer stemlike cells are key to cancer development and therapy. The MYC‐interfering polypeptide, Omomyc, impairs the carcinogenic potential of human glioblastoma stemlike cells (GSCs) and affects proper MYC genomic localization. This indicates that the gene regulatory nodes determining GSC identity are MYC dependency.


MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc—a MYC‐derived polypeptide interfering with MYC activity—taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC. This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.

Synopsis

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Cancer stemlike cells are key to cancer development and therapy. The MYC‐interfering polypeptide, Omomyc, impairs the carcinogenic potential of human glioblastoma stemlike cells (GSCs) and affects proper MYC genomic localization. This indicates that the gene regulatory nodes determining GSC identity are MYC dependent.

Omomyc occupies DNA E‐boxes targeted by MYC network complexes, weakening the gene expression programme control nodes and facilitating phenotype changes in the presence of appropriate stimuli.

Expression of Omomyc in GSCs—in vitro and in xenografts—rebalances their transcriptome towards differentiation and tumour suppression by affecting the transcript levels of master transcription factors and key non‐coding RNAs.

Blunting MYC activity by Omomyc restrains GSC tumorigenic features—self‐renewal, proliferation, differentiation, migration and tumour vascularization—in vitro and in vivo by both cell‐autonomous and non‐cell‐autonomous mechanisms.

1) How would you introduce the background to your research to someone who is completely unfamiliar with your field?
Neurogenesis is the process underlying brain development and it is executed by the neural stem cells, which generate neurons and glial cells. The proper regulation of neurogenesis requires that neural stem cells divide to amplify the population of cells in the growing brain. However, it also requires that these cells differentiate into mature neurons upon proper stimuli. The balance between these two activities is essential to achieve the right number of neurons without depleting the neural stem cells population. Such balance is achieved through a fine regulation of cell metabolism and gene expression. One layer of such regulation involves flexible processing of precursor messenger RNAs to yield multiple proteins from each gene. Several RNA processing factors modulate these mechanisms in the developing brain. One of them, SAM68, is highly expressed in neural stem cells and it was previously implicated in the pathogenesis of neurodegenerative diseases.
 
2) What exact question did you set out to answer?
SAM68 expression oscillates during mouse brain development, with a peak at times of intense neurogenesis and a sharp decline after birth. This observation suggested that SAM68 might be involved in the regulation of neurogenesis. Thus, we set out to investigate its role during brain development in mouse embryos.
 
3) What is the most important finding of your paper?
We found that the expression levels of SAM68 dictate the fate of neural stem cells. High expression promotes their self-renewal and amplification of the stem cell pool; low expression triggers their differentiation into neurons. We also linked SAM68 function to regulation of Aldehyde Dehydrogenase 1A3 (ALDH1A3) expression, an enzyme that fuels glycolytic metabolism in stem cells. We discovered that SAM68 binds an alternative polyadenylation signal in the ALDH1A3 transcript, preventing its premature termination and insuring expression of a functional enzyme. Thus, our study identifies SAM68 as a key regulator of neural stem cell self-renewal through maintenance of high glycolytic metabolism.
 
 
4) What is the most important next step and/or future challenge that follows on from your paper?
RNA metabolism plays a major role in brain development regulation and is often altered in neurodegenerative and intellectual diseases. Our future goal is to investigate whether functional defects in SAM68 are involved in such pathologies and to develop tools to rescue the molecular defects underlying them.
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​Dipartimento di Biomedicina e Prevenzione
Università di Roma Tor Vergata 

presso Facoltà di Medicina e Chirurgia
Indirizzo:  Viale Montpellier, 1 – Roma
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Prof. Antonio De Lorenzo


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