Research

The extracellular matrix (ECM), a complex meshwork of cross-linked proteins, is a fundamental component of multicellular organisms. It provides architectural supports to the cells, confers mechanical properties to tissues, and conveys biochemical signals transduced by cell-surface receptors to control various cellular processes such as proliferation, survival, differentiation, adhesion and migration. Alterations in the composition and organization of the ECM cause or accompany the development of diseases such as fibrosis, cardio-vascular diseases, and cancer (Naba et al., Nat Rev Mol Cell Biol, 2024).

To explore the importance of the ECM in diseases, our lab has developed transformative proteomic and bioinformatic approaches to study the molecular composition of the ECM - or the "matrisome" - of normal and diseased tissues.

Using these approaches, we discovered that the ECM of any given tissue is composed of 150+ different proteins, and that the composition of the ECM varies between tissues, between normal tissues and tumors arising from them, between tumors of different metastatic potentials, and between primary tumors and their distant metastases. Importantly, our pipeline is a powerful tool to devise hypothesis-driven research, since it has led to the discovery of a novel ECM protein called SNED1 (Naba et al., eLife, 2014).

Projects currently ongoing in the lab include:

Project 1: Developing proteomic methods for deep matrisome profiling

While our work has contributed to make proteomics a state-of-the-art approach to study the global composition of ECM of tissues, many aspects of the ECM remain to be discovered, including which ECM protein isoforms or which post-translational modifications are present in different pathophysiological contexts. As of today, we are still unable to  characterize the ECM interactome in situ and we are far from achieving 100% sequence coverage using classical proteomic approaches (Bains and Naba, Exp Rev Prot, 2024). We are thus pursuing the development of enhanced methods to achieve what we term "deep matrisome profiling".

We have recently received NIH funding to pursue the following projects: 


Project 2: Understanding the roles of the novel ECM protein, SNED1, in development, health, and breast cancer metastasis

We previously identified a novel ECM protein, SNED1 (Sushi, Nidogen and EGF-like domain protein 1), in a proteomic screen aimed at discovering ECM proteins differentially expressed between highly and poorly metastatic mammary tumors. We reported that SNED1 was produced only by highly metastatic tumor cells, and not by poorly metastatic tumor cells or by stromal cells, and that it played a functional role in tumor dissemination, as, SNED1 knockdown decreased metastasis in a murine model of breast cancer. We further showed that the level of expression of SNED1 was a prognostic factor for hormone-negative breast cancer patients (Naba et al., eLife, 2014). Our goal is to identify the cellular and molecular mechanisms controlled by SNED1 contributing to breast cancer metastasis. We are also interested in evaluating the prognostic value of SNED1's expression for human cancer patients.

The importance of SNED1 in breast cancer metastasis prompted us to evaluate the role of SNED1 in development and physiology. To do so, we generated the first knockout mouse model of Sned1 and showed that Sned1 is an essential gene, since its deletion leads to early neo-natal lethality due to severe craniofacial malformations  (Barque et al., Dev Dyn, 2020). 

In collaboration with the laboratory of Dr. Sylvie Ricard-Blum (University of Lyon 1, France) we published the first biochemical and biophysical characterization of SNED1 and showed that SNED1 is a fibrillar protein of the ECM capable of interacting with multiple other ECM and transmembrane proteins (Vallet et al., Biochem J, 2021). Our current work focuses on deciphering the mechanisms of SNED1 fibrillogenesis and the impact of SNED1 on cellular processes involved in embryonic development, with a focus on craniofacial morphogenesis. 

We have recently received NIH funding to pursue the following projects: 


Collaborative projects

Through collaborative efforts, and robust external funding, our lab also continues to develop novel proteomic approaches and bioinformatic tools to further characterize the ECM of tissues in different patho-physiological contexts.