PC INTERACTOME

Assembly of a prostate cancer genome-wide molecular interactome for the identification of the key regulatory genes of malignant transformation and new targets for therapeutic intervention

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 Obiettivo del progetto (Objective)

'A major issue in the translation of findings from mouse models to clinical practice is the lack of appropriate tools to identify causal mechanisms of oncogenesis, tumor progression, and drug activity. The multidisciplinary project here proposed will characterize fundamental mechanisms and signaling pathways deregulated in prostate cancer through the assembly of a prostate cancer interactome, which is an accurate network of transcriptional and post-translational molecular interactions. Importantly, we will utilize reverse-engineering approaches that are unbiased and encompass the entire genome. We will use gene expression profiling of samples from different mouse models in order to have a representation of all the stages of the disease. This novel mouse to human paradigm will allow distinguishing the “drivers” of prostate cancer from the large number of “passenger” genes whose expression is coincidentally rather than causally altered in cancer progression. Key regulators will then be validated by expression analyses in mouse and human prostate cancers tissue micro-arrays to assess their relationship to disease aggressiveness and outcome. Finally, interrogation of this interactome will allow the identification of novel druggable targets for prostate cancer therapy. Candidate targets will be identified focusing first on those genes that can modulate particular signaling pathways deregulated in prostate cancer, and second on candidate targets that may induce tumor-cell specific apoptosis. Next, we will validate the expression of these candidate targets in human prostate cancer specimens, thus allowing the identification of the individuals that might benefit from specific interventions. The integrated in vivo modeling and bioinformatics study on prostate cancer proposed here will improve the capacity of the European host institution of conducting cutting edge research on this area and should constitute a significant step forward in the European leadership in the field.'

Introduzione (Teaser)

EU-funded researchers have identified novel factors involved in prostate cancer (PC) onset and progression through studies on mouse models. This could revolutionise and personalise the clinical management of cancer patients.

Descrizione progetto (Article)

Researchers comprehensively characterised the PC interactome (PCi) during the course of the project PC INTERACTOME. PCi refers to the entire genome network of transcriptional and post-translational molecular interactions that occur during PC progression.

Researchers successfully generated the mouse PCi using data from 14 different genetically engineered mouse (GEM) models. They compiled almost 400 gene expression profiling datasets with genetic, phenotypic and pharmacologic diversity. Using the 'Algorithm for the reconstruction of accurate cellular networks' (ARACNe) algorithm, one of the project partners developed the datasets.

Combining chromatin immunoprecipitation and DNA sequencing the scientists validated results from the PCi predictions. Comparison of all the selected transcription factors (TFs) such as BCL6, MYC, AR and ER as well as their targets revealed a significant overlap.

A mouse model of metastatic cancer was used to identify phenotypic variations that are linked to aggressive cancers. Extensive characterisation of mouse model was carried out and published in a peer-reviewed journal (Proceedings of the National Academy of Sciences of the United States of America, PNAS).

PC INTERACTOME compared metastatic with non-metastatic tumours and revealed master regulators involved in cancer progression that could be useful biomarkers for predicting disease outcome. In particular, the expression levels of forkhead box M1 (FOXM1) and centromere protein F (CENPF) were tested in silico along with studies on prostate cancer specimens.

Gene silencing experiments revealed that synergistic activation of FOXM1 and CENPF was found in more aggressive forms of PC. Patients with higher levels of FOXM1 or CENPF proteins had higher chances of survival than those with elevated levels of both these proteins.

Studies on PC cell lines helped identify altered signalling pathways that are associated with FOXM1 and/or CENPF. An important finding was the identification of signalling pathways relevant to tumourigenesis following co-silencing of FOXM1 and CENPF. This included the MAP kinase pathway and PI3 kinase signalling pathway. Scientists also successfully identified genes involved in the enrichment of such signalling. The assembly of the human and mouse interactomes, as well as all the biochemical and functional validation studies leading to the identification of FOXM1 and CENPF as master regulators of prostate cancer aggressiveness were published in a peer-reviewed journal (Cancer Cell).

Project outcomes have set the stage for more effective PC management. Novel therapeutic targets may result using the knowledge generated during the project.