PI: Valérie Trichet (MCU), Pierre Layrolle (DR Inserm)

Philippe Rosset (PU-PH), Pierre Perrot (PU-PH), Louis-Romée Le Nail (PH)

PhD student: Louise Marchandet

Engineers and technician: Bénédicte Brulin (IE Inserm), Benoît FRONT (TECH CDD INSERM)

Master 2 students:

Key words: Stromal Cells, Cancer Stem Cells, Bone tumors, 3D culture, Bioprinting

Mesenchymal stromal/stem cells (MSCs) are part of the tumor microenvironment and they may promote tumor growth. We have shown that MSC derived from adipose tissue or from bone marrow have a supportive role in osteosarcoma development (Perrot et al, Plos One 2010; Avril et al, Journal of Bone Oncology 2015 and Plastic Reconstructive Surgery 2016). Moreover, we have shown that the tumor potential of MSC with few oncogenic hits may be enhanced by a mixture of pesticides at low doses (Hochane et al, Stem Cells 2017).

Cancer Stem Cells (CSCs) are characterized by self-renewal, pluripotency as normal stem cells and have the ability to initiate tumor. CSCs may explain some treatment resistance and tumor recurrence. The mesenchymal origin of CSCs in Ewing's sarcoma appears well supported. In contrast, osteosarcoma is thought to derive either from MSC which have gone bad leading to CSC or from committed cells such as osteoblasts which have acquired mesenchymal cell properties during the malignant process. To answer this question, stem cell-like cells from osteosarcoma biopsies are compared to MSCs derived from bone marrow of patients.

To understand the reciprocal interaction of MSC and bone tumor cells, cells are grown in 3 dimensional culture models such as oncospheroids, organotypic sections and bioprinting. We have developed osteoid tissues by growing MSCs on mineral granules (Gamblin et al, Acta Biomater 2014) or on micro-fiber scaffolds (Brennan et al, Biomedical Materials 2015). We are developing 3D bioprinting of bone tumors using bio inks in order to mimic cell-cell and cell-matrix interactions. 3D Bioprinting will help for the development of new therapies against cancers being an intermediate technology platform between traditional 2D monocellular cultures and animal models.

3 main questions:

  • What is the role of MSC in the bone tumor niche?
  • Could MSC represent the origin of primary bone tumor by forming a pool of cancer stem cells (CSC)?
  • How to test drugs on 3D tumor microenvironment in vitro?

Fundings, networks

Major recent publications:

  • Le Nail LR, Brennan M, Rosset P, Deschaseaux F, Piloquet P, Pichon O, Le Caignec C, Crenn V, Layrolle P, Hérault O, De Pinieux G, Trichet V. Comparison of Tumor- and Bone Marrow-Derived Mesenchymal Stromal/Stem Cells from Patients with High-Grade Osteosarcoma. Int J Mol Sci. 2018. 1;19.
  • Hochane M, Trichet V, Pecqueur C, Avril P, Oliver L, Denis J, Brion R, Amiaud J, Pineau A, MSC. Naveilhan P, Heymann D, Vallette FM, Olivier C. Low-Dose Pesticide Mixture Induces Senescence in Normal Mesenchymal Stem Cells (MSC) and Promotes Tumorigenic Phenotype in Premalignant. Stem Cells. 2017.
  • Avril P, Duteille F, Ridel P, Heymann M-F, De Pinieux G, Gouin F, Rédini F, Blanchard F, Heymann D, Trichet V, Perrot P. Opposite effects of soluble factors secreted by adipose tissue on proliferating and quiescent osteosarcoma cells. Plastic Reconstructive Surgery, 2016.
  • Avril P, Le Nail L-R,Brennan MA , Rosset P, De Pinieux G, Layrolle P, Heymann D, , Perrot P, Trichet V. Mesenchymal stem cells enhance proliferation but do not change quiescent state of osteosarcoma cells: different implication before and after tumor resection. Journal of Bone Oncology, 2015.
  • Brennan M, Renaud A, Gamblin A, D'Arros C, Nedellec S, Trichet V, Layrolle P. 3D cell culture and osteogenic differentiation of human bone marrow stromal cells plated onto jet-sprayed or electrospun micro-fiber scaffolds. Biomedical Materials, 2015.
  • Gamblin AL, Renaud A, Charrier C, Hulin P, Louarn G, Heymann D, Trichet V, Layrolle P. Osteoblastic and osteoclastic differentiation of human mesenchymal stem cells and monocytes in a miniaturized three-dimensional culture with mineral granules. Acta Biomater, 2014.
  • Perrot P, Rousseau J, Bouffaut AL, Rédini F, Cassagnau E, Deschaseaux F, Heymann MF, Heymann D, Duteille F, Trichet V, Gouin F. Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS ONE 2010.