Team leader

Sabine Bailly Laboratory of Biology and Biotechnologies​ for Health CEA-Grenoble 17 avenue des Martyrs 38 054 Grenoble cedex 9 Phone: 04 38 78 92 14 Fax: 04 38 78 50 58

Members of the team

Valentin Azemard, IE INSERM Sabine Bailly, DR1 INSERM Léa Beurier-Soulat, Licence-pro Claire Bouvard, MC UGA Agnès Castan, IR1 INSERM Nicolas Chaumontel, CEA Technician Sophie Dupuis-Girod, MD, HCL Lyon Nicolas Ricard, INSERM Researcher Yasmin Rida, PhD Student Florence Rivera, CEA Researcher Aude Salomon, IE INSERM Emmanuelle Tillet, UGA Prof. Léa Vialet, PhD Student ​

Tumoral angiogenesis		BMP9/BMP10/ALK1 signaling

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Introduction

Angiogenesis and lymphangiogenesis, which correspond to the formation of new blood and lymphatic vessels from existing vessels, are two major processes involved in physiological development, but also in tumoral development and metastatic dissemination. Since now ten years, anti-angiogenic treatments have been developed in order to asphyxiate the tumour or to inhibit metastasis but the results so far are not as promising as we thought. The understanding of how these new vessels are formed is thus very important for the development of new therapeutic approaches.

To address this question, our team is working since 2002 on a new signalling pathway specific to the vascular system mediated by the transmembranous receptor ALK1 (activin receptor-like kinase 1). ALK1 is a serine/threonine kinase type 1 receptor of the TGFß family that is specifically expressed on endothelial cells. Several studies obtained in man and mouse support its critical role in vascular development:

1. Mutations in the gene encoding ALK1 (ACVRL1) are associated to two vascular rare defects:
   - The Rendu-Osler (RO) disease, also known as hereditary haemorrhagic telangiectasia (HHT2) (Johnson et al.,1996)). HHT is characterized by telangiectasia, epistaxis (nose bleed) and arterio-venous shunts in the liver, the lungs and the brain that can lead to death in the more severe cases. Mutations in endoglin, a co-receptor for ALK1 are also responsible of another form of HHT (HHT1). The clinical signs are very similar to HHT2 supporting the key role of this signalling pathway for vascular integrity.

- The pulmonary arterial hypertension (PAH) (Harrison et al.,2003). PAH is characterized by a progressive obliteration of the pulmonary arteries leading to hypertension and right heart failure.
2. The inactivation of the gene encoding Alk1 in mice leads to embryonic lethality (E11.5) due to severe vascular defects (Oh et al.,2000 ; Urness et al.,2000).

Projects

The aim of the team is to continue the study of the involvement of ALK1 and its ligands, BMP9 and BMP10 in blood and lymphatic vascular development in order to propose new therapeutic approaches in vascular diseases and cancer. For this, we are developing the following axes of research:

1) Study of the respective roles of BMP9 and BMP10 in blood and lymphatic development

2) Study on the involvement of BMP9 and BMP10 in the two vascular diseases involving ALK1:
- hereditary haemorrhagic telangiectasia (HHT)/Rendu-Osler disease
- Pulmonary arterial hypertension (PAH)

3) Study of the involvement of BMP9 and BMP10 in cancer and metastasis: ALK1 as a therapeutic target.


Keywords

Angiogenesis, Lymphangiogenesis, BMP and TGFß signaling, HHT, PAH, Cancer


International collaboration: TGFß and Chagas disease