Barbara Garmy-Susini: Spotlight on the Lymphatic Vascular System

The lymphatic system, which ensures waste disposal and the immune surveillance of many tissues, is less well-known than its counterpart, the blood system. Barbara Garmy-Susini, from the Institute of Cardiovascular and Metabolic Diseases in Toulouse, has been working to remedy this injustice for the past 15 years. How does the lymphatic system work? How should it be treated when treatment is needed? In order to answer these questions, she has received support from the European Union.

Barbara Garmy-Susini, Inserm Research Director at the Institute of Cardiovascular and Metabolic Diseases (I2MC) in Toulouse, has received €8 million as part of the European Union’s Horizon 2020 program. Her project, Theralymph, is aimed at developing gene therapy for lymphedema – a disease of the lymphatic vascular system. This funding represents a much-anticipated mark of recognition for the scientist, who has sometimes had to clash swords in order to see her research through. A native of Toulouse, her journey began when she enrolled in biology at Université Paul-Sabatier out of personal conviction. « Teachers would say that research was without prospects, she acknowledges. But the lab internships I did from the second year reassured me in my choice » Against all odds, she stuck with it. « It was during my master’s degree at Sanofi Toulouse that I discovered the endothelium [the layer of cells that line the vessels, Ed.] » she adds. Drawn to this tissue, she decided to make it the subject of her dissertation. With this in mind, in 2000, she joined the laboratory of Jean-François Arnal, doctor and researcher, who back then was the head of an Inserm team at Rangueil University Hospital. There she studied the protective effect of estrogens – the female sex hormones – on the endothelium before menopause. What is more, the laboratory took a medical approach to physiology: a cross-disciplinary dimension that was to mark the next steps in her journey.

In 2004, having completed her dissertation, she wanted to do a postdoctoral fellowship in an English-speaking country « in order to be bilingual, » she says, preferably in the United States. But her spouse had professional ties to Toulouse. « There were two options: either we could go to the States together or I could choose a position less than an hour’s flight away so that we could see each other at weekends, she remembers. We had to make a decision. » The couple finally opted for San Diego and Garmy-Susini joined Judith Varner’s laboratory at the University of California to study the role of the endothelium in cancer. Just one year after her arrival, she made a major discovery, which was published in a prestigious journal: The Journal of Clinical Investigation. She showed that integrins – endothelial adhesion molecules – grip tumor cells, enabling them to anchor themselves within the tissues.

Doing the groundwork and inventing tools

« No longer under pressure to publish at the end of my postdoc, I took Judith Varner’s advice and studied lymphatic vessels, on which nobody was working at the time, » she adds. These vessels, present in almost all tissues, are responsible for collecting interstitial fluids – fluids located between the cells and blood capillaries – as well as fats and immune cells, before joining the bloodstream. This study represented a major challenge: « Very few tools were available, especially when it came to differentiating lymphatic vessels from the blood network. Everything had to be invented! » For three years, she did the groundwork for the subject at a frenetic pace, adding to her family at the same time. « Raising three young children without the help of family became complicated, » she acknowledges. In 2009, we decided to return to France. » 

Anne-Catherine Prats, who at that time was working at the Cancer Research Center of Toulouse (CRCT), hosted her for a postdoctoral fellowship on the molecular biology of lymphatic vessels. « It was an essential encounter, both professionally and personally, » emphasizes Garmy- Susini. But three months after my arrival, the approval of the laboratory was not renewed. Although I did not have a support team, I did pass the competitive examination to become an Inserm research fellow. » She then she joined a CRCT team specializing in pancreatic cancer and which showed, for the first time, that cancer cells disperse within the body by regulating the transcription of genes linked to the lymphatic network for their own benefit. After four years, the researcher, who had major publications and funding under her belt,decided to set up her own team. « The Director of I2MC in Toulouse, Angelo Parini, opened his doors to me, where I created my team and was back working in proximity with Anne-Catherine Prats, who was the institute’s Deputy Director. » 

Towards gene therapy for lymphedema

Today, the team has 22 researchers and doctors who take a cross-disciplinary approach, studying the lymphatic system from different angles. They have been the first to map pathological lymph remodeling following a myocardial infarction. « We were the first to analyze the effect of estrogens on the lymphatic system, » adds the researcher. Then we studied lymphedema, or elephantiasis, which causes limb swelling to such an extent that amputation is sometimes needed. » Thisdisease, which affects over 250 millionpeople worldwide, is caused by the filarialparasite, genetic abnormalities,and cancer treatments. In fact, « 15% of women who have had breast cancer then go on to develop lymphedema of the arm on the side that was treated, » she says. On the one hand, the team is attempting to identify early markersof lymphedema in order to be able to use physiotherapy to prevent its development. On the other hand, ithas launched Theralymph, a major project fundedby Europe. With 11 European partners, and in collaboration with Rangueil University Hospital’s vascular medicine department headed byAlessandra Bura-Rivière, the researchersare developing a gene therapy based ontwo distinct RNAs. One will code for a growthfactor of the lymphatic vessels,the other will restore otherfunctions, such as vascular contraction.« The first treatment evaluation phase in patients will begin in 2023, » she says. This represents hope for patients, vascular doctors and breast cancer surgeons. « We still have to convince oncologists but we are taking it day by day!  » For now, Garmy-Susini is focusing on her current projects and the young researchers around her. « I place, co-opt and support them, as I would like people to have done for me, » concludes the researcher who – finally – no longer has to fight to convince the academic sphere of the relevance of the lymphatic vascular system.

Note:
*unit 1048 Inserm/Université Toulouse III-Paul Sabatier, Molecular regulation of lymphangiogenic factors in cardiovascular diseases team, I2MC