Role of mesenchymal stem/stromal cells (MSCs) in the microenvironment
Model system: interactions between MSCs and cancer cells
Regulation of the energetic metabolism
The microenvironment plays a crucial role for cell biological functions and tissue homeostasis. It regulates processes like placental implantation during pregnancy, it also plays an essential role for pathologies such as cancer. This microenvironment contains several components: diffusible soluble factors, elements of the extracellular matrix and cells. We are interested in identifying the mechanisms that allow the control of cell functions by the microenvironment.
In a model of human placental implantation, using coculture systems between explants of human placenta and and human primary endometrium fibroblasts, we previously showed the role of fibronectin splicing and of TGFb1 cytokine secretion by the endometrium fibroblasts in the regulation of trophoblast invasion (Lopez et al., 2013; Fafet et al., 2008).
Contrary to trophoblast invasion, that is regulated in time and space, tumor progression becomes uncontrolled. Mesenchymal stem/stromal cells (MSCs) are recruited to tumor sites, principally due to their inflammatory status. Interactions between MSCs and cancer cells lead to changes in tumor progression and in the cancer cell response to therapeutic agents. A whole panel of cytokines involved in these effects are now known. Very recently, different research groups – including ours – showed that MSCs also communicate with various cell types by direct interactions, via nanotube-like structures.
To study direct interactions between MSCs and cancer cells, we developed a coculture system (both 2D and 3D) between human MSCs (from the French EFS) and the MDA-MB-231 human breast carcinoma cells. With this coculture system, we could show that MSCs can transfer mitochondria to MDA-MB-231 cells. The transfer of MSC mitochondria to cancer cells leads to modifications of their energetic metabolism and metastatic potential.
The main goals of our research projects are the following:
1. Regulation of the mitochondria transfer from MSCs and future of the transferred mitochondria within cells
2. Characterization of the cell energetic metabolic reprogramming following MSC mitochondria transfer
3. Characterization of the transcriptional reprogramming following MSC mitochondria transfer, effects on cell proliferation
4. Determination of the impact of MSC mitochondria transfer on cell survival in response to therapeutic agents.
The transfer of MSC mitochondria opens new perspectives for the role of the microenvironment on cell behavior and response to external stimuli.
Coculture between human MSC (red mitoTracker) and MDA-MB-231 cancer cells (green CellTracker) (Scale10 µm)
- Caicedo et al. Metabolic reprogramming of cancer cells by artificial transfer of mitochondria from human mesenchymal stem/stromal cells (submitted for publication).
- Lopez-Mejia I.C. et al. 2013. Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion. Mol Biol Cell, 24, 3164-3176.
- Fafet P. et al. Opposite effects of TGFß activation and ROCK inhibition on human trophoblast migration in a reconstituted placental-endometrial coculture system. Endocrinology (2008) 149, 4475-85.
tel: 04 99 63 60 26
adress: INSERM U844, Hôpital Saint Eloi, bat INM, 80 rue Augustin Fliche, BP-74703, 34091 MONTPELLIER - Cedex 5, FRANCE
VIGNAIS Marie-Luce (CR1-CNRS)
CAICEDO Andrés (PhD-MRT-FRM)
DENNEMONT Indira (M2)
AYALA Mickaël (M1)
Mesenchymal stem/stromal cells (MSCs)
Technics - Know-how
Real-time confocal imaging
2D and 3D cocultures
Mitochondrial activity (SeaHorse)
3D invasion tests