Lymphangiogenesis and microenvironment
From bed side to bench: lymphangiogenic niche in primary tumor and lymph nodes
Most carcinomas metastasize primarily to lymph nodes. The nodal status is a key parameter that helps to define the patient prognosis and the global treatment plan. The translational study coordinated by A. Noel. and Dr. F. Kridelka (Department of Gynecology-Obstétric, CHU) aims at giving new insights into lymphatic network remodeling in primary cervical cancers and in lymph nodes and to explore the “dialogue” between these 2 structures. The clinical objective is to identify prognostic indicators for post-surgical treatment through a selective nodal dissection focusing on the most representative and most at risk lymph node for metastasis.
For mechanistic investigation, an original in vivo model has been set up to reproduce such a pre-metastatic lymphangiogenic niche in lymph nodes. Gelatin sponges containing tumor cells are implanted in mouse ears rich in lymphatic vessels. This system allows to study the process of lymphangiogenesis in primary tumor (in the ear), as well as the lymphatic compartment in sentinel lymph nodes at pre-metastatic and metastatic stages. This new model offers a unique opportunity to provide key information that can be validated on human lymph node samples
Garcia-Caballero et al, 2017; van de Velde et al, 2018
Recently, we indentified novel regulators of lymphangiogenesis: MMP-2 and uPARAP.
We have discovered a new regulator of VEGFR-2/VEGFR-3 signalization in LEC whose function in vascular biology was unknown: uPARAP. It is member of the mannose receptor protein family, which plays a key role in the collagen turnover process governed by mesenchymal cells. We have collected evidence that uPARAP genetic deletion (in vivo, in 3 different models) or downregulation (in vitro) leads to overgrowth and hyperbranching of lymphatic vessels in pathological conditions. This original study paves the way for novel development in the design of strategies controlling lymphatic functionality, especially in cancer or related secondary lymphedema.
Detry et al., 2012 ; Durré et al., 2018;
Towards improvement of targeted therapies
Breast cancer is a highly prevalent cancer in women around the world, among which basal like or/and triple-negative breast (TNBC) cancers are heterogeneous cancers with poor prognosis. Their high expression level of EGF receptor (EGFR) offers a unique opportunity to develop treatment based on monoclonal antibodies or tyrosine kinase inhibitors. Although these approaches have shown promise in some cancers, single agent therapy is ineffective in unselected TNBC and response of patients are often limited or transient due to the acquisition of resistance. We previously discovered that MT4-MMP, a membrane-type matrix metalloprotease, colocalizes and interacts with EGFR in TNBC cells. The clinical relevance of our findings was demonstrated through a collaboration with Pr Guy Jerusalem (Medical Oncology, CHU), Dr NE Sounni and Pr Ph Delvenne. Importantly, we discovered that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.
Chabottaux et al., 2006; Paye et al., 2014; Yip et al., 2017; Foidart et al., 2019
Carcinoma-associated fibrobasts (CAF) as key actors of the tumor microenvironment
The tumor stroma is no longer perceived as a physical support for cancer cells, but it is now demonstrated as an important driver of tumorigenicity. Within the tumor microenvironment, heterogenous populations of fibroblastic cells, called carcinoma-associated fibroblasts (CAFs), are key players of the tumor progression and have diverse origins, phenotypes and functions. We have identified two subsets of CAFs : 1) one issued from bone marrow-derived mesenchymal stem cells that express the pro-invasive MMP13 and 2) one expressing α11 integrin and PDGFRβ, which exert paracrine effect on cancer cells by producing tenascin C, a pro-invasive matrikine. We also showed that juxtacrine interactions between bone marrow-derived mesenchymal stem cells and cancer cells stimulate proliferative and invasive properties of cancer cells through AREG shedding.
Lecomte et al., 2012; Carnet et al., 2015; Primac et al., in press
Ocular diseases
Angiogenesis and lymphangiogenesis are key step processes shared byt multiple pathologies, including cancer development but also some ocular diseases. In our lab, we take advantage of studying complex cellular processes in different and complementary pathological model, such as corneal diseases and age-related macular degeneration --> see Vincent Lambert section.
Lambert et al., 2013; Lecomte et al., 2011; Detry et al., 2013;
