Descripción del proyecto
Resistencia a la transformación oncogénica
Las células cancerosas surgen a partir de una combinación de alteraciones genéticas y epigenéticas en las células normales, que fomentan su transformación. Sin embargo, las señales oncogénicas pueden ser inocuas en algunas células, lo cual sugiere la existencia de un mecanismo que protege de la transformación celular. Mediante «Drosophila» como modelo, los científicos del proyecto financiado con fondos europeos OncoResist investigarán la proliferación de células epiteliales en el ojo tras una señalización del hipotálamo anormal. El trabajo se centrará en los cambios producidos en el entorno nuclear como la accesibilidad de la cromatina y el papel de los ARN largos no codificantes. La descripción de este mecanismo protector abre nuevas vías de investigación contra el cáncer.
Objetivo
Oncogenesis is a complex multi-step process that involves the combination of genetic and epigenetic alterations for normal cells to turn into cancerous cells. Remarkably, while some strong oncogenic signals can promote transformation in some cell states, they are completely innocuous to other cell types.
My aim is to study this poorly understood phenomena, being my current hypothesis, that intrinsic cell state transformation protection mechanisms are likely to exist.
I will use the Drosophila eye primordium epithelium, as I have previously observed that whereas committed epithelial cells over-proliferate in response to abnormal Hippo signalling, undifferentiated progenitor cells are resistant to this transformation.
To molecularly define such resilience to oncogenesis, the gene expression and chromatin accessibility profile of these two cell populations were compared. My preliminary results showed that the chromatin accessibility profile differed significantly and suggested that some pioneer transcription factors primed cells to respond to Hippo signalling. Moreover, I observed that non-coding RNAs were differentially expressed between these two cell populations. In particular, some long non-coding RNAs (lncRNAs), a class of molecules that were recently described as regulators of oncogenic signals, were particularly enriched in the progenitor cell population.
More specifically, I aim to address two main questions:
1 - Is the nuclear landscape (chromatin accessibility and TFs combinations) important to control the response to high oncogenic signals? And how much of this response relies on the activity of pioneer transcription factors?
2 - What is the role of the lncRNAs in controlling cellular response to Hippo signalling?
A better understanding of the intrinsic cell state protective mechanisms against transformation is likely to open important new therapeutic approaches for cancer.
Ámbito científico
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
3810-193 Aveiro
Portugal