While on summer vacation in Bologna, Jaap den Toonder received some surprising and exciting news. After his initial grant proposal was put on the reserve list, he received an email with news that he has been awarded an ERC Advanced Grant to study the process of intravasation - the process by which cancer cells pass through blood vessel walls and spread to other parts of the body.
"We had just visited the University of Bologna that same morning," says Jaap den Toonder with evident delight in his email. "And we celebrated with a very good glass of wine!"
Den Toonder , who is full professor in the Department of Mechanical Engineering and chair of the Microsystems section , was enjoying a nice lunch with his family in a restaurant in Bologna when the email with news of the ERC Advanced Grant arrived in his mailbox.
Cancer intravasation
The topic of Den Toonder's project will tackle a problem with significant health implications. Cancer is a major cause of mortality, with almost 10 million deaths due to cancer recorded in 2020. Den Toonder will use the ERC Advanced Grant to study a critical step in how cancer cells spread in the body.
"The most devastating thing about cancer cells is the ability to spread in a process known as metastasis," says Den Toonder.
There are several steps in metastasis such as invasion (when cancer cells invade surrounding tissue from a primary tumor), circulation (when cancer cells travel through the bloodstream), and colonization (when cancer cells grow and form secondary tumors at other locations in the body).
Put simply, if we can stop cancer cells from passing through blood vessel walls, then we can stop the spread of cancer.
Jaap den Toonder
To travel through the body via the bloodstream, cancer cells need to pass through blood vessel walls via a process known as intravasation.
"There are a lot of unknowns about intravasation, even though it is so relevant to how cancer cells spread. Put simply, if we can stop cancer cells from passing through blood vessel walls, then we can stop the spread of cancer," noted Den Toonder.
A major question that Den Toonder wants to answer is whether cancer cells enter blood vessels individually or as a group. "It's advantageous for cancer cells to metastasize as a group, but for the intravasation part this is counter intuitive. Do cancer cells temporarily separate from each other and then pass through the walls one-by-one?"
Project Intrap
In Den Toonder's project titled 'Microfluidic platform for cancer Intravasation: pass or no pass?' or Intrap for short, he will explore the mechanics of how cancer cells enter blood vessels.
"Current research on cancer cells indicates that intravasation is influenced by a range of mechanical properties, such as cell stiffness, geometry and sticking interactions. This isn't surprising as to pass through the blood vessel walls, the cancer cells need to deform, detach from the vessel wall, and overcome mechanical forces between themselves and their surroundings," says Den Toonder.
To study the various mechanical properties and how they influence the motion of cancer cells, Den Toonder plans to develop a brand new microfluidic or cancer-on-a-chip (CoC) experimental setup.
"In the past, we have studied how breast cancer cells move towards artificial blood vessels on such a chip. In Intrap, we are leaping forward with the design by accounting for the factors that influence intravasation such as blood flow rate, the curved geometry of vessels, and how cells stick to each other."
A particularly innovative aspect of the new setup is that Den Toonder will use it used to study how multiple mechanical properties affect cancer cells at the same time. "This will increase the speed with which we can study the importance of different mechanical factors, and it will save lots of time over the course of the research study."
The groundbreaking result
For Den Toonder, the groundbreaking result of Intrap will be the creation of an intravasation phase diagram that shows how intravasation depends on properties such as cancer cell stiffness, blood flow pressure, shear stress on the walls caused by blood flow, the radius of the blood vessel, and the porosity of the cell layer that lines the inside of the blood vessels.
"I call this 'a pass-no-pass phase diagram' and it will be an extraordinary result if produced over the course of the project," says Den Toonder.
To enable Den Toonder to study the intravasation process up close and in real time, he will also use some of the grant to invest in an advanced microscope for live cell imaging of cancer cells as they move into the blood vessels on the chips.
A pass-no-pass phase diagram will be an extraordinary result if produced over the course of the project.
Jaap den Toonder
"I've been granted more than half a million euros extra on top of the regular budget of €2.5 million to purchase a microscope for live imaging. This piece of equipment will be a huge asset in the laboratory for the researchers working on this project."
In addition, Den Toonder will be hiring a team of young researchers for the Intrap project, made up of four PhD researchers and two Postdoctoral researchers. The project will last for five years.
Second ERC Advanced Grant
For Den Toonder, this is his second ERC Advanced grant, which is very rare given the low success rate of applications for such a prestigious grant.
"It is a great honor and recognition for the research that our team has been doing to date! It means a lot to me and gives me the opportunity to start a large new project on a completely different topic than the one covered by my first ERC Advanced Grant."
In his first ERC Advanced Grant-funded project, Den Toonder and a team of researchers created magnetic artificial cilia, inspired in part by how these hairs vibrate in nature. These hairs can be used in microfluid devices and sensors, and contributed in part to the TU/e spin-off ARTIC Technologies .
I feel very lucky to get a second chance to pursue groundbreaking work once again.
Jaap den Toonder
"An ERC Advanced Grant is one of the few large grants that enables independent fundamental science - financing the type of research that can lead to truly groundbreaking results that can have great impact on a longer timescale. I feel very lucky to get a second chance to pursue groundbreaking work once again."
