Agence Nationale pour la Recherche

18-IBHU-0003 (2019-2026)

THEMA – Leukemia on Chip

The global aim of this project is to decipher the cellular and molecular mechanisms regulating the interaction of leukemic blasts with bone-marrow stromal cells. We have recently found that hematopoietic stem cells polarize in contact with these stromal cells by forming an anchoring structure that is reminiscent of immunological synapse. Our aim here is to study whether this polarization could be affected in leukemic cells, and perhaps impacting two key behaviors: anchorage versus migration and quiescence versus proliferation. The main hypothesis is that the “hematopoietic synapse” prevents cell migration and maintains cell quiescence.

          The experimental strategy is to analyze leukemic cells interactions with bone-marrow stromal cells using quiet innovative microfluidic devices that have been developed in our lab: a bone-marrow-on-a-chip that recapitulates both 3D structural and biochemical composition of endosteal and vascular niches. Indeed, the scheme consists on an investigation within the bone marrow emulation confronting leukemic stem cells (LSC) versus hematopoietic stem cells (HSC). Several models, comprising 1- Acute Myeloid Leukemia (AML) murine models, 2- AML human cell lines, 3- patient derived xenografts and 4- patient samples are to be used. It is planned to measure cell polarity and monitor cell behavior as well, using live-cell video-microscopy in the bone marrow-on-a-chip circuit. Thus, this potent tool will provide a quantitative measurement of LSC migration and proliferation in contact with stromal cells. Finally we will analyze whether LSC have an impact on the niche and whether the crosstalk between LSC and the niche could be druggable.