PRIMES

PRIMES: Protein interaction machines in oncogenic EGF receptor signalling

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 Obiettivo del progetto (Objective)

'PRIMES focuses on the role of protein interactions to assemble dynamic molecular machines that receive and process information to coordinate cellular responses. PRIMES investigates the following: (i) How do protein interactions contribute to the generation of biological specificity in signalling? (ii) How do pathogenetic perturbations affect protein interaction networks? (iii) How can we exploit protein interactions as therapeutic targets? We focus on the EGFR/ERBB signalling network and its role in colorectal cancer (CRC), the third most frequent cancer. The ERBB network is frequently altered in CRC either through overexpression or mutation of the receptors or downstream components. Network components have become important drug targets. Poor response rates and resistance demonstrate we lack sufficient insight to design efficacious therapies. Using proteomics, structural biology, advanced imaging and mathematical modelling we (i) map static and dynamic protein interactions in the ERBB network (ii) unravel the design principles and emergent network properties conferred by protein interactions; and (iii) validate these findings in genetic mouse models of CRC and human tissues. PRIMES aims to (i) enhance the functional pathogenetic understanding of CRC (ii) identify mechanisms of drug resistance and drug efficacy; and (iii) identify drugs that affect protein interactions to rationally manipulate network functions related to individual genetic mutations. Outcomes include (i) a dynamic, mechanistic flowchart of how protein interactions compute biochemical and biological specificity in signalling networks (ii) a functional protein interaction network of healthy and oncogenic ERBB signalling validated in mouse models of CRC and human tissues (iii) network level insights towards personalised CRC treatment based on genotype-phenotype relationships; and (iv) chemical compounds targeting protein interactions to restore normal ERBB network function or break oncogenic circuits.'

Introduzione (Teaser)

Deconstructing the molecular interactions in cancer cells could lead to the discovery of novel drug targets. A European consortium is looking at how the dynamic interactions among proteins drive oncogenic signalling.

Descrizione progetto (Article)

The epidermal growth factor receptor (EGFR/ErbB) regulates key developmental processes including cell proliferation and differentiation. Aberrant EGFR signalling is encountered in many cancers suggesting that it may play a central role in disease onset or progression.

The EU-funded 'Protein interaction machines in oncogenic EGF receptor signalling' (http://www.primes-fp7.eu/ (PRIMES)) study focuses on the role of EGFR signalling in colorectal and breast cancer and in particular on protein interactions. Researchers will employ a combination of techniques including fluorescence imaging, proteomics and mathematical modelling. They aim to analyse both static and dynamic protein interactions within the EGFR pathway and elucidate their role.

The PRIMES experimental outline entails the use of natural ligands or drugs to perturb signalling. The functional outcome is observed using imaging microscopy and proteomics. Similar experiments will be performed by interfering with the expression of particular network proteins.

The work so far has led to the delineation of an interactive network of 55 proteins. Scientists developed the Mammalian Membrane Two-Hybrid (MaMTH) method to identify receptor-interacting partners including novel players in oncogenic EGFR signalling. MaMTH demonstrated low false negative rates and facilitated the monitoring of protein-protein interactions. Receptor modifiers have also been identified and their role in modulating EGFR responses is being evaluated. To predict the outcome of protein interactions and recapitulate the EGFR network, scientists are developing suitable assays and mathematical models.

To add clinical relevance to the work, project findings will be validated in cancer mouse models and patient samples. From a therapeutic perspective, the PRIMES consortium will identify chemical compounds that target protein interactions via different mechanisms through high-throughput screening of small compound libraries.

The PRIMES study will significantly improve our knowledge on the role of protein interactions as signal processing machines in cancer. Equally importantly, the project deliverables will help design new, efficacious, targeted therapies to overcome the poor therapeutic responses and resistance observed with traditional drugs.