Unravelling genome alterations during tumour progression

A new systems biology approach to cancer is studying the development of the disease from an earlier stage than ever – before the tumour has even started. Dr Bruno Amati, a Group Leader at the European Institute of Oncology in Milan, is the Coordinator of MODHEP, an international Research Program that aims at providing unprecedented understanding of genome organisation and function from the earliest stages of tumour progression, combined with unrivalled systems-level modelling of the process.

Cancer, as the long-running search for preventative therapies will testify, is a highly complex, multi-stage disease involving several genetic and epigenetic events that interact over a long period of time. While we now have a better understanding of the latter stages of cancer, we know precious little about the early ones. Studying the complex processes of these early stages is made all the harder as primary tumours become obscured by secondary and tertiary ones, unable to be identified by traditional analysis.

MODHEP (MODelling HEPatocellular carcinoma) a network of 13 partners in 7 countries, is the first research project to take an integrated systems biology approach to the issue – a 360-degree, multi-layered analysis of genome organisation and function, based on several central assumptions. Firstly, that cancer is driven not only by genetic alterations (i.e. mutations in the DNA directly affecting cancer genes) but also by epigenetic ones (i.e. stable alterations in gene function that are not due to mutations, and may alter different levels of genome organisation). Secondly, that cancer cannot be modelled without detailed information on the preneoplastic (pre-tumour) stage; Thirdly, that systems modelling of tumour progression from clinical samples is unrealistic due to lack of access to the early stages of the disease; Fourthly, that cell heterogeneity constitutes an important limitation to molecular analysis of tumour samples; and Fifthly that many of the driving events, early-stage mutations and interactions are invisible with classical analysis and therefore need to be identified using a systems approach, at a much earlier stage.

With these assumptions in mind, MODHEP is studying the development of liver cancer in mice, to give the clearest view of the process at every stage. “Although our early-stage analysis is the first of its kind, we actually use two traditional mouse models for the study,” says Dr Amati.

“Liver cancer in mice, being one of the easiest types to view and manipulate due to the homogeneity of the hepatic tissue, offers us unique access to the different stages of the disease – we can see it developing live, right from the earliest stages, in a way that would be impossible with traditional clinical tumour samples.”

Mouse model 1, the Transgenic Tumour Model, allows researchers to see how cancer progresses by activating an oncogene (a gene that has the potential to cause cancer) specifically in hepatocytes.

Mouse model 2 uses a mouse strain lacking the gene coding for the glycoprotein Mdr2 (Multi-drug resistance 2): this causes Chronic Inflammation of the liver, leading to the onset of cancer. Indeed, inflammatory conditions are a typical cause of liver cancer in humans. Model 1 therefore involves direct genetic modification of a cancer gene, while model 2 does not, but reproduces a typical condition underlying cancer progression in patients.

It’s a pioneering approach that combines classical models with the latest technology, including state-of-the-art imaging equipment, advanced methodology for the study of chromosome organisation, as well as “next generation” DNA sequencing technology, to deliver a level of analysis only dreamed of before.

The 13 partners collaborate to offer specialist techniques and technologies towards that analysis and to build mathematical models of the process - something that Dr Amati says is already showing promise even at this early stage of the project.

“We only started at the beginning of 2011 – we’re still in the set-up phase, so it’s much too early to talk of any results yet,” he says. “But what we have seen already is the excellent level of collaboration and the efficient workflow within what is a very diverse and international network. We now have a system that is providing levels of analysis that no one has ever seen before in this area of research and we would hope to have initial data for analysis in about three months, which is very exciting. I’m extremely proud of the way MODHEP is coming together.”

Aside from the European Institute of Oncology in Milan, where Dr Amati is based, partners in the project include research institutes across Italy, France, the Netherlands, Germany, the UK, Israel and Japan. MODHEP brings together elite scientists from a complimentary range of biology fields, including genetics, chromatin regulation, genomics, and liver cancer, alongside those in computational and systems biology.

It’s this collaborative aspect, says Dr Amati, which has been vital for the project’s holistic, systems biology approach to study a range of complex biological interactions and create accurate mathematical modelling. “The project relies on each partner to provide a particular expertise, whether it’s a biological specialism, cutting-edge technology or mathematical and computational analysis.”

It’s certainly been an encouraging start, so where does Dr Amati hope the research can go from here? “Well the ultimate aim is to identify those molecules that act as critical “nodes” in disease progression and maintenance, which may thus constitute the Achille’s Heel, if you wish, of the cancer cell.”

“Providing we can generate the large amount of data needed for mathematical modelling of the disease, I would hope to have an identification of those critical molecules, as well as their pre-clinical validation as therapeutic targets in our mouse models of liver cancer by the time the project ends in 2015 – that would be a great success, paving the way for clinical development of targeted therapies.”

That is promising news, given that liver cancer remains one of the most common forms of the disease and, because it is largely incurable, one of the most devastating. Furthermore, Dr Amati feels that results against this form of cancer, could bring help with others. “If our research is successful, we feel that its fundamental principles could be applied to other cancers, too, so potentially the benefit across the range of cancer types could be huge.”

Dr Amati has also been encouraged by the integration of multiple levels of genome and epigenome analysis based on the latest technologies and a modern systems approach, a combination that is the essence of the project. “I hope that MODHEP will establish the great advantages of working in this way, and that this will become a blueprint for this kind of research in future. It will allow us to analyse the processes and functions of multi-stage cancer at a level we have never been able to before.”

It’s another great example of a European-led research project that is adopting a revolutionary approach to tackling two of the most challenging aspects of cancer research today - understanding which are the weak points of a given type of tumour, and finding those vital early signs of the disease before the patient is even aware it has begun.

Published: Thursday, 29th September 2011