MICROENVIMET

Understanding and fighting metastasis by modulating the tumour microenvironment through interference with the protease network

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 Obiettivo del progetto (Objective)

'The MICROENVIMET project proposes innovative approaches for building a comprehensive understanding of the interplay between cancer cells and their microenvironment both at primary and secondary sites. The objectives are to identify molecular pathways involved in the regulation of metastatic dissemination to lung, liver, lymph node and bone. To achieve these objectives, the original experimental approach proposed is to modulate the production/activity of proteases or their inhibitors. Proteases are now recognized as key regulators of a complex network of interacting molecules that modulate the properties of cancer cells and their microenvironment. The project is intended to identify key molecular pathways underlying early steps of metastatic dissemination by interfering with the protease network and studying the impact of such experimentally manipulated microenvironment on metastasis formation. In addition to identifying key regulators of metastasis, we aim at developing blocking antibodies towards these new candidates, with efficacy for therapeutic intervention, by using the most advanced state-of-the-art technologies. The study of cancer stem cells will be integrated into current concepts that consider and attempt to explain the importance of the microenvironment during cancer progression. The 9 academic and 1 SME Participants will combine expertise in genomics, proteomics, bioinformatics, in vivo imaging, transgenic mice, mouse models of metastasis, genetic manipulation of transplantable tumour cells, computerized image analysis, virus-mediated gene transfer, phage display and production of neutralizing antibodies. This consortium will facilitate shared access to a new microRNA platform, innovative technologies, human tumour tissue banks, in vivo and in vitro models mimicking different steps of metastatic dissemination, as well as know how in tumour-host cell interplay, angiogenesis, lymphangiogenesis, cancer stem cell biology and generation of database.'

Introduzione (Teaser)

Failure of diverse clinical approaches to alleviate metastatic spread of neoplastic disease indicates that the process of metastasis is not sufficiently understood. A European study was designed to examine the role of the metastatic niche by investigating the nature and molecular pathways involved.

Descrizione progetto (Article)

The ability of cancer cells to colonise tissues and form new tumours, a process known as metastasis, represents the hallmark of cancer and the major death determinant of cancer patients. Understanding the metastatic dissemination of cancer is vital for designing effective treatment strategies.

By taking into account a variety of cellular and non-cellular factors in the microenvironment within the primary and secondary tumour site, the Microenvimet project was based on the concept that the microenvironment is decisive for tumour progression. In line with this aim, the consortium used innovative approaches to study the interplay between cancer cells and their microenvironment.

In particular, project scientists focused on the network of proteases, enzymes responsible for various cellular functions. They combined the most advanced state-of-the-art technologies for identification of gene signature with in vivo and in vitro gene manipulation, proteomic analysis and in vivo imaging of metastatic cells, with the aim of obtaining a global view of the metastatic process.

The use of a metastatic model of breast cancer led to the identification of small non-coding RNAs which were modulated during cancer progression. Modulation of the tumour microenvironment revealed a protective effect of some protease members (matrix metalloproteinases) produced by host cells and the contribution of cathepsins in the recruitment of host cells in primary tumours, as well as cancer growth and metastasis.

With the aim of developing an anti-metastatic therapy, the consortium characterised neutralising antibodies and developed nanoparticles for the delivery of protease inhibitors. The efficacy of these strategies was demonstrated in vivo in the breast cancer model.

This approach was extended to human monoclonal antibodies against two membrane-bound proteins, one expressed by tumour cells and one produced by stromal cells contributing to the microenvironment. Evaluation of these molecules as therapeutic drugs will reveal the potential of the approach to become translated into clinical practice.

Collectively, the work by the Microenvimet project underlines the complexity of the molecular network involved in the tumour microenvironment. At the same time, it demonstrates the need to gain an in-depth understanding of the metastatic process for efficient cancer eradication.