Peering deeper into the ‘matrix’

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The extracellular matrix, which surrounds our cells, has a profound impact on how cells behave and is important in the progression and spread of cancer. Now, researchers have developed an intuitive new way to dissolve cells away from tissues, leaving behind the unaltered matrix. The new approach makes it possible to view the intact matrix – and to catalogue its components – in unprecedented detail in 3D. Using the new approach, the team has already shown that the matrix around tumours differs substantially from organ to organ.

Journal/conference: Nature Medicine

DOI: 10.1038/nm.4352

Organisation/s: Garvan Institute of Medical Research

Funder: Danish Cancer Society Novo Nordisk Foundation European Research Council Consolidator Award Ragnar Söderberg Foundation Sweden Cancerfonden Sweden Innovation Foundation Denmark National Health and Medical Research Council (NHMRC) Australia Danish Council for Independent Research

Media Release

From: Garvan Institute of Medical Research

Scientists from the Biotech Research & Innovation Centre (BRIC) at the University of Copenhagen have developed a groundbreaking method to reveal the structure of tissues and tumours with unprecedented detail, by completely dissolving away cells and leaving the delicate extracellular matrix intact.

The matrix surrounds the cells in every organ of our bodies, and provides shape and structure to the organ. The matrix has a profound impact on how cells behave, and so controls the progression of diseases such as cancer – yet the matrix is extremely difficult to study in detail.

Now a team of researchers led by Professor Janine Erler has developed a new technique – published in Nature Medicine today – that makes closer study of the matrix possible. The technique reveals the inner structure of organs and tumours by removing cells but leaving the matrix completely unaltered. The three-dimensional structure of this matrix has never been seen in such detail before.

“We have developed a technique to obtain intact organ scaffolds and to image them in incredibly high detail using microscopes. We are the first to image the 3D structures of primary and metastatic tumours as well as healthy organs in this way,” says Professor Erler.

Developed in mice post mortem, the technique is the first to use existing blood vessels to deliver cell-removing compounds directly to a specific tissue or organ.

The new method was pioneered by postdoctoral fellow Dr Alejandro Mayorca-Guiliani, in Professor Erler’s team, who says, “We have isolated the structure that keeps tissues in place and organises the cells inside them. We did this by using existing blood vessels to deliver cell-removing compounds directly to a specific tissue to remove all cells within an organ. Doing this leaves behind an intact scaffold that could be analysed biochemically and microscopically, providing us with the first view of the structure of tumours.”

Imaging expert and co-first author Dr Chris Madsen (now at Lund University, Sweden) says, “When you remove the cells, the clarity of what you can see through the microscope is much improved – you can see the fibres of the matrix more clearly and you can look much deeper into the tissue. Using this approach, we have been able to see important differences in matrix organisation when we looked at metastatic tumours in the lung and in the lymph node.”

Matrix biology and mass spectrometry expert and co-first author Dr Thomas Cox (now based at the Garvan Institute of Medical Research, Sydney) says, “Because we are removing the cells completely, we can use mass spectrometry to identify and catalogue the components of the matrix – in normal tissue and in tumours – in unprecedented detail. What is really exciting is we found that some of the components of the matrix in different secondary tumours [metastases] are unique to that tissue. That is telling us that remodelling of the matrix in cancer is organ-specific.”

This research is an advance in the fields of both cancer research and bioengineering: By using the decellularised organs one can learn much more about how tumours and normal organs are built, and what their differences are. This new technique might even have an impact on organ regeneration and tissue engineering in the future.

“We are now re-introducing cells into our extracellular matrix scaffolds, bringing them back to life, to study how tumours form and how cancer progresses. This is extremely exciting and offers a unique opportunity to study how cells behave in their native environment,” explains Professor Erler.

The research is supported by the Danish Cancer Society, an ERC Consolidator Award, the Novo Nordisk Foundation, a European Research Council Consolidator Award, the Ragnar Söderberg Foundation Sweden, Cancerfonden Sweden, the Innovation Foundation Denmark, the National Health and Medical Research Council (NHMRC) Australia and the Danish Council for Independent Research.


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