Noémie Brassard-Jollive, doctoral student in oncology

What is the focus of your research team ?

We study blood vessels - essentially capillaries, the smallest vessels in the body - in normal or pathological contexts, such as cardiovascular disease or cancer.
My team is made up of four people : the laboratory director, a doctor and two other researchers, including my thesis supervisor. There are also two technicians and three PhD students, including myself.
My focus is on kidney cancer, and more specifically its most common and aggressive subtype, clear cell kidney cancer. Specifically, I'm interested in how tumor cells interact with blood capillaries.

Why associate tumor cells with blood capillaries ?

A tumor is a mass of varying size caused by the excessive and abnormal multiplication of cells. To grow, it stimulates the formation of capillaries from surrounding blood vessels to supply it with what it needs : nutrients and oxygen. I'm interested in this formation of vessels at tumor level, according to three aspects :
- How is vascularization formed ?
- How do tumor cells behave in contact with this vascularization ?
- What is the effect of treatments commonly used in kidney cancer on tumor mass and blood capillaries ?

What is the distinctive feature of clear-cell kidney cancer ?

In 80 % of cases, this disease is due to an alteration in a gene called VHL. This mutation favours the formation of extensive vascularization and the invasion of tumour cells. As a result, clear-cell kidney cancer is an extremely aggressive tumour, growing rapidly and metastasizing. Metastasis is the result of cancer cells having acquired the ability to pass into the bloodstream and colonize other organs. For patients, the survival associated with this cancer is dramatically low : research to find new treatments is a major challenge.

Is there no drug capable of treating this cancer ?

Anti-angiogenic treatments are the main therapies for this cancer. They use molecules that inhibit angiogenesis, i.e. the formation of blood vessels, thus preventing the tumor's blood supply. The tumor no longer receives the nutrients it needs, and the cancer cells die.
This treatment can slightly extend the life expectancy of patients with very advanced clear-cell kidney cancer. Unfortunately, escape and resistance have been observed : some patients respond to the treatment, then stop responding, while others never respond at all. A whole area of research is focused on understanding the mechanisms of resistance that render treatment ineffective.

This is where your research comes in..

We have demonstrated that the blood vessels which irrigate tumours in clear cell kidney cancer have particular morphologies and dimensions compared with vessels in other cancers : they are very long and flat, or very wide and dilated. To study this so-called aberrant vascularization and the response of these vessels to anti-angiogenic treatments, we have developed an in vitro model - outside the living organism, and in three dimensions.
This model consists of spherical clusters of tumor cells, called spheroids, held in biological hydrogels that contain endothelial cells. These are specific cells that organize themselves to form blood vessels.
For the first time, we are mimicking in vitro and in 3D the aberrant vascularization of this kidney cancer. Technologically, this model is innovative and represents an interesting alternative approach to current preclinical models. In the longer term, since this model mimics what is observed in the patient, it could be relevant to use it to test new drugs targeting the specific vascularization of this kidney cancer.

How do you make these vascularized microtumors ?

Using tumor cells and endothelial cells, I use gravity to form 3D spheroids of tumor cells in droplets, which I then embed in a biological hydrogel containing endothelial cells. This hydrogel is deposited inside microwells located in culture dishes. This cellular engineering was the first part of my thesis. I do this under a microbiological safety station, a protection system that enables me to carry out my manipulations under sterile conditions.
Developing three-dimensional models is crucial. For a long time, we studied cancer cells in vitro in two dimensions, and it turns out that this does not represent what can happen in our own bodies, which have the third dimension !
I also do a lot of imaging on fluorescent cells. This allows me to observe them under the microscope, to visualize whether they are invasive or not, to analyze the formation of capillaries in the tumor... Then, I analyze the images using 3D reconstruction software in particular.
The first time I generated vascularized microtumors was on a Sunday in the lab. The optimal experimental conditions hadn't yet been defined, but we were keen to carry out a first test. Finally, the microscopic result was magnificent: the spheroids were completely vascularized. At first, I didn't believe it at all, but the success was all the greater.

What did you study after the baccalauréat ?

Initially, I wanted to work in a more technical field. So I enrolled in a DUT in biological engineering, a two-year course that enables you to become a laboratory technician or assistant engineer. I loved it : there was a lot of practical work, but also a lot of theory.
Then I did my first research internship, on tumor angiogenesis. This was no accident : I already wanted to go into oncology.
I liked the theory as much as the technical side, so I went on to the University of Paris-Diderot (now the University of Paris) for a third year of a bachelor's degree, where I studied mainly cell biology. This led to a more enlightened choice for my next step, which was a master's degree at Pierre-et-Marie-Curie University (now Sorbonne University), the second year of which was spent in Stéphane Germain's team, where I'm currently doing my thesis.
Starting with a DUT enabled me to work in stages, feel the difficulties and gauge my level of involvement. I was increasingly motivated by what I was learning, so I said to myself : why not continue ? In the end, I don't regret it.

Where are you now and what have you learned ?

I'm now at the end of my thesis : I still have scientific articles to write, but also a lot of experiments. To complete them, I'm helped by a technician who works in my team. It's really great to be able to work in pairs like this.
When I started out, I was maybe doing too much, it was pretty intense. A PhD in biology often involves delicate experiments that require regular monitoring : it's hard to take it easy, not to stay out too late in the evening or not come in at the weekend.
The thesis is a big part of my daily life, but I keep it in perspective. I play sports : running, swimming, boxing... at least four times a week. It's important for me : it allows me to clear my head. I'm also passionate about literature, and I got married in the second year of my thesis. Managing to keep these activities going at the same time has shown me that a balance between professional and personal life is essential to remain productive.

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Noémie Brassard-Jollive works at CIRB, under the supervision of Catherine Monnot, in the Rôle des protéines de la matrice dans l'hypoxie et l'angiogenèse team, headed by Stéphane Germain. Her thesis is entitled " Vascularized 3D tumor spheroids reveal invasion strategies governed by microenvironment properties and aberrant vascular architecture ".

Photos © Patrick Imbert
Interview by Océane Alouda