Researchers have developed a method that enables them to more easily study the extracellular matrix scaffolds that hold organs together. This may improve understanding of the spread of metastatic cancer and lead to new treatments.
All our organs comprise extracellular matrix scaffolds colonised by living cells.
These scaffolds signal how the cells need to organise themselves in the scaffold, and the cells themselves construct the scaffold by pumping structural proteins into their surroundings.
A healthy extracellular matrix scaffold instructs healthy cell behaviour, whereas a diseased scaffold instructs diseased cell behaviour.
Consistently, diseased cells act more normally in a healthy extracellular matrix scaffold, and healthy cells act unhealthily in a diseased scaffold. However, both types of cells gradually try to modify the scaffold in a healthier or unhealthier direction. For example, cancer cells alter healthy scaffolds to enable the rapid growth of the cancer cells and enhance their ability to spread to new sites.
The extracellular matrix scaffolds could not previously be studied in a realistic way to improve insight into various diseases. However, researchers have developed a method using a mouse model, isolating an organ, removing the cells from the organ and placing the scaffold in a box with liquid flowing in and out, to use the scaffold as a bioreactor to study cell activities under a microscope.
The research, which opens up completely new avenues for investigating disease and the effects of drug treatment, has been published in Advanced Healthcare Materials.
“Once we put the extracellular matrix scaffold in the special bioreactor in the laboratory, we can study much more easily what happens when, for example, cancer cells colonise it, as they do in metastatic cancer. This will improve understanding of the mechanisms underlying the development of metastasis and perhaps also how to develop drugs to prevent metastasis in other organs,” explains the senior researcher behind the study, Janine Erler, Professor and Group Leader, Biotech Research & Innovations Centre (BRIC), University of Copenhagen.
Developing methods to study organs in 3D
In the study, lead researcher Alejandro E. Mayorca-Guiliani, Assistant Professor in the Erler Group, developed a microsurgical operation for isolating a mouse organ, decellularising it and transferring the remaining extracellular matrix scaffold to a special bioreactor chamber so that cells flow back into the scaffold and study the cells in detail under a microscope.
Researchers have been studying organ scaffolds for many years, but the problem has been that this has happened in petri dishes, where the scaffolds are flat and not in their natural 3D structure.
The new method changes all this.
Once the researchers remove the mouse organ, they decellularise it with a solvent that dissolves all the cells and leaves only the extracellular matrix scaffold, which maintains the structure and shape to the organ.
The researchers then transfer the scaffold to the special perfusion bioreactor in which they can control the temperature and the flow of oxygen and nutrients and repopulate with cells.
“The great advantage of our system is that it is flexible. Metastasis threatens people with cancer and is very difficult to study. Our model can use organ scaffolds from various organs and cells of various origins and with various gene mutations, enabling new experimental opportunities to study the mechanisms of metastatic cancer and other diseases,” says Alejandro E. Mayorca-Guiliani.
Studying how cancer cells affect the scaffold
The researchers used the new method to study metastatic cancer cells more easily. They inserted cancer cells into the extracellular matrix scaffold to investigate how they attach themselves to the scaffold, establish themselves and change the scaffold to serve other purposes.
Putting the cancer cells in the scaffold is equivalent to them detaching from one place in the body and being transported through the bloodstream to another location where they establish themselves as a metastatic tumour.
The cancer cells mimic this process in the special bioreactor containing an organ extracellular matrix scaffold.
“The cancer cells in our model system can also make the changes seen in real tumours. Further, in the extracellular matrix scaffold in the bioreactor chamber, the cancer cells act as they do in the real world,” explains Janine Erler.
Can be used to study the effects of drugs
Janine Erler explains that the model system can become very relevant in developing anti-cancer drugs.
For example, researchers can study how cancer cells interact with the extracellular matrix scaffold in the lungs and thereby better understand what the cancer cells need to grow and how a drug can neutralise this process.
The cancer cells may use specific signalling pathways to modify the structure of the extracellular matrix scaffold so that they can grow in it. Drugs that can block these signalling pathways may be a potent remedy for cancer or at least metastasis, which often makes cancer lethal.
Researchers can also use the model system to test drug candidates for efficacy.
“The most relevant application of our system is studying the effects of drugs. Many anti-cancer drugs target the signalling of cancer cells, and our system can be used to determine how a drug affects tumour formation in the lungs and to study the effects in other diseases. Examining how the body itself acts towards a healthy or diseased extracellular matrix scaffold may also be relevant. For example, what do the cells of the immune system do in one situation or another?” says Janine Erler.
She elaborates that the first models use mouse organs, but the aim for the next step is to work with human tissues. This will make studying potential drugs even more clinically relevant.
“This system may be very useful for screening drugs, determining their effects on organ-specific tumours or on many types of diseases,” concludes Prof Janine Erler.