BMP, Ecosystem, stemness and dynamic in cancer

Objectives

The projects of our lab focus on Bone Morphogenetic Protein (BMP) family members, stem cells, and the tumor niche.

We study the effect of the tumor environment on Cancer Stem Cells (CSCs) and their resistance to treatment, using epithelial tumour models and haematopoietic models. Our approach relies on analyzing and modulating the expression of these BMP family members and characterizing their functions.

We are developing projects subjecting cancer stem cells to different conditions, which will allow us to evaluate the impact of their interactions with the microenvironment on their ability to resist treatment.

We are also studying the functional consequences, in terms of drug response, of interactions between CSCs and cellular or structural components of the tumor niche, by integrating the physical and environmental parameters with, for example, the mechanical constraints.

Projects

Previous work

Our work has led to a number of advances in the field of Bone Morphogenic Proteins (BMPs) and stem cells (SCs).  Our work focuses on the hematopoietic system and the mammary gland. We have shown that FLRG regulates hematopoietic stem cells (HSC) by blocking members of the TGFβ family (Activin and certain BMPs), or directly by promoting the regulation of HSCs through adhesion to fibronectin. BMP4 alone regulates the entire megakaryopoiesis, for example mediated by Thrombopoietin (TPO), the effects of which are largely mediated by the autocrine BMP loop. We were further able to demonstrate that chemotherapies alter the relationship between the SC and its microenvironment, the so-called niche. We have shown that in chronic myeloid leukemia (CML), Twist1 is a predictive marker and plays a role in drug resistance. To analyze the epithelial system of the breast, we have developed a simple strategy to isolate human mammary SCs and identified a key role for the enzyme CD10 and β1 integrins in their regulation by their niche, further showing that CD10 is a marker for stem and early progenitor cells that form spheres.

(A) Mammopshere obtained from primary human mammary epithelial cells isolated from reduction mammoplasty. (B) Immunofluorescent staining of keratin 14 of a mammosphere. (C) Hematopoietic stem cell in its niche. (source: Internet Google Image) (D) Terminal ductal lobular unit assay. Phase contrast image of 3D structures obtained from mammary stem and progenitor cells grown in matrigel (left) and H&E staining of a cross section of a lobular unit (right). (E) Erythroid (top) and megakaryocyte (bottom) colonies derived from human hematopoietic stem cells.

Résumé des projets

From a clinical point of view, it is essential to eliminate cancer stem cells responsible for resistance and relapse. Our group and others have demonstrated that BMP molecules, members of the TGFβ superfamily, are key regulators of SCs and their niche in both normal and tumoral contexts. In order to analyze the role of the BMP pathway in the regulation of cancer stem cells (CSCs), we use two models: Chronic Myeloid Leukemia (CML) in a hematopoietic system which constitutes the standard model for the transformation of normal SCs and breast cancer in an epithelial system forming solid tumors, in which the existence of CSCs has been demonstrated but the origin of which remains unknown.

Our preliminary data indicate that, in these two CSC models, there is a deregulation in the BMP pathway. We hypothesized that, as is the case in glioblastoma, an alteration in the BMP signaling pathway and the cellular biological response in the blood and the breast is required to maintain the CSC phenotype and resistance. This could constitute a general mechanism of appearance of CSCs and resistance. We suggested that the deregulation of the BMP pathway could be due to different alterations linked to the various functions of the BMP family and may not necessarily be identical between the different tissues affected. We are testing this hypothesis in our models, using the molecular tools we have developed and are examining the effect of BMP deregulation on CSC appearance and properties such as quiescence, self-renewal, proliferation, differentiation, adhesion, migration, tumorigenic potential, and therapeutic resistance. We are particularly interested in the contribution of the microenvironment towards the maintenance of CSCs (such as the enzymatic function of CD10), resistance and escape from therapies. Lastly, we are currently exploring whether the links between BMP molecules and immune cells may contribute to the escape of CSCs from the immune response. This project is befitting of the wider aim of the lab to explore the role of CD10 and BMPs in the transformation of mammary SCs.

Our medium-term goals are to improve our understanding of the specific mechanisms governing the resistance of SCs and to develop a model system that allows the evaluation of novel targeted therapeutic strategies against SCs in the context of their environment.