Lung cancer and inflammation
Mechanisms of cancer dissemination towards lung tissue
This part of our research program aims at deciphering the mechanism implicating ADAM/ADAMTS proteases in lung cancer or in cancer dissemination towards the lungs, the role of lung microenvironment modifications and the impact of environment (mostly air pollution) on tumor development in lung tissue.
Effects of Ozone-induced inflammation on lung metastasis
Air pollution is responsible for 400 000 deaths each year in the European community and includes ozone (O3) as one of the most detrimental compounds.
We aimed to outline the mechanisms through which pulmonary O3 exposure and subsequent O3-induced lung neutrophils modulate metastasis kinetics in an experimental mouse model. We recently demonstrated that pulmonary neutrophils induced by ozone promote metastatic dissemination. This manuscript is in revision for publication in Thorax (IF = 10).
Mechanisms implicating a deregulation of the microenvironment of the lung
1.b.1. Importance of inflammation-generated extracellular matrix fragments in lung metastasis
Different clinical studies support the link between chronic inflammation and higher cancer dissemination to specific tissues. Using different tumor models, we showed that neutrophilic inflammation established locally in the lungs triggers lung metastasis. We demonstrated for the first time that the tripeptide N-acetyl-Proline-Glycine-Proline (ac-PGP) chemotactic fragments generated by the action of neutrophil-derived MMP9 on collagen fibers leads to increased lung metastasis.
Role of ADAM28 in cancer progression
An inhibition of ADAM28 is cancer cells was shown to inhibit tumor growth. In order to understand the role of ADAM28 produced by host cells, we generated genetically engineered-mice fully deficient for ADAM28 and we observed that they display unexpectedly increased lung colonization by pulmonary, melanoma or breast tumor cells. Our data highlight a functional role of ADAM28 in T cell mobilization and point to an unexpected protective role for host ADAM28 against metastasis. This manuscript is in revision for Oncotarget.
Mechanisms of mesothelioma progression and resistance to therapies
The unique line of chemotherapy for malignant mesothelioma is based on cisplatin/pemetrexed combination and associated with disappointing response rate. A better understanding of chemoresistance mechanisms might change paradigms in mesothelioma management. We reported higher ADAM10 expression levels in human MPM samples and confirmed ADAM10 overexpression was also observed in murine MPM samples. With in vitro an in vivo experiments, we demonstrated that ADAM10 is a potential target in mesothelioma and this work is currently in revision to be published in Oncogene.
Pharmaceutical developments (collaboration with CIRM and UCL)
Pharmaceutical developments of inhaled medications dedicated to airways diseases are an important part of our activities and generate synergies with our other projects.
