Discovery of a molecule that can regulate the formation of lymphatic vessels
The team of Professor Agnès Noël (Director of GIGA-Cancer) has discovered a molecule capable of regulating the formation of lymphatic vessels in cancers. This discovery has just been published in the prestigious journal Nature Communications.
This work is the result of research initiated in the framework of a European project coordinated by Professor Agnes Noël and involving the gynecology department of the University Hospital of Liège (Professor Frédéric Kridelka) and Finnish and Danish collaborators.
The lymphatic vessels form a vascular network parallel to the blood vessels. The lymphatic system plays a central role in all immune responses. In cancers, the lymphatic vessels provide a pathway for tumor cells to leave the primary tumor and colonize the lymph nodes. The presence of tumor cells in the lymph nodes is a key factor used clinically to determine the prognosis and the treatment plan to be applied. Regulating their function by blocking them should therefore make it possible to prevent the formation of ganglionic metastases.
Conversely, another pathology, called lymphoedema, is linked to a lack of formation of lymphatic vessels. This is the accumulation of fluid that induces local tissue swelling or swelling of a limb. This may be the case, for example, after certain surgical procedures that damage the lymphatic vessels and induce the formation of a large arm or a large lower limb. In this case, it is the stimulation of lymphatic vessels that would be beneficial for the patient.
The discovery of a new regulator of the formation of lymphatic vessels thus offers new perspectives to block these vessels and treat cancers, or conversely to stimulate and treat lymphoedema. This advance is important since no treatment currently exists to inhibit or stimulate the lymphatic system.
Abstract
The development of new lymphatic vessels occurs in many cancerous and inflammatory diseases through the binding of VEGF-C to its receptors, VEGFR-2 and VEGFR-3. The regulation of VEGFR-2/VEGFR-3 heterodimerisation and its downstream signaling in lymphatic endothelial cells (LECs) remain poorly understood. Here, we identify the endocytic receptor, uPARAP, as a partner of VEGFR-2 and VEGFR-3 that regulates their heterodimerisation. Genetic ablation of uPARAP leads to hyperbranched lymphatic vasculatures in pathological conditions without affecting concomitant angiogenesis. In vitro, uPARAP controls LEC migration in response to VEGF-C but not VEGF-A or VEGF-CCys156Ser. uPARAP restricts VEGFR-2/VEGFR-3 heterodimerisation and subsequent VEGFR-2-mediated phosphorylation and inactivation of Crk-II adaptor. uPARAP promotes VEGFR-3 signaling through the Crk-II/JNK/paxillin/Rac1 pathway. Pharmacological Rac1 inhibition in uPARAP knockout mice restores the wild-type phenotype. In summary, our study identifies a molecular regulator of lymphangiogenesis, and uncovers novel molecular features of VEGFR-2/VEGFR-3 crosstalk and downstream signaling during VEGF-C-driven LEC sprouting in pathological conditions.
Reference
uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis
Nature Communicationsvolume 9, Article number: 5178 (2018)
