A majority of cancer cells rely on a specific type of metabolism characterized by a high level of glycolysis occurring in aerobic conditions and leading to a high amount of lactate production. This so-called Warburg effect or aerobic glycolysis is also observed during specific stages of embryonic development such as the preimplantation embryo, or in embryonic stem cells. The physiological significance of this unusual type of energy metabolism during development and in cancer is not understood. Our preliminary observations in mouse and chicken embryos indicate that precursor cells of muscles and vertebrae exhibit aerobic glycolysis with high levels of lactate production much as is observed in cancer cells. Skeletal muscles and vertebrae derive from an embryonic tissue called paraxial mesoderm, which is produced as the body axis forms by posterior elongation. One striking characteristic of the paraxial mesoderm is it segmentation into repeated structures called somites that give rise to the vertebrae and associated structures. While aerobic glycolysis is often considered to be associated to fast proliferating cells, the situation appears more complex as in the paraxial mesoderm, only cells experiencing high levels of Wnt and FGF signaling exhibit aerobic glycolysis. Blocking glycolysis in developing chicken embryos leads to axis truncation as is observed in the Wnt or FGF pathway mutants. In the posterior paraxial mesoderm, FGF signaling controls glycolysis which in turn controls Wnt signaling. In this project, we propose to explore in detail the role of energy metabolism in the control of body formation and segmentation in vivo in chicken embryos and also in vitro in mouse and human pluripotent cells differentiated toward a paraxial mesoderm fate. More specifically, we want to characterize the aerobic glycolysis taking place in the posterior paraxial mesoderm to see how it relates to the Warburg effect of cancer cells. The physiological significance of Warburg effect in cancer is not understood. The identification of the counterpart to this physiological state in the embryo might help shed light on the role of this particular metabolic strategy and lead to a better understanding of cancer physiology. We will also explore the crosstalk between FGF, glycolysis and Wnt signaling in the developing paraxial mesoderm, and the role of this specific type of glycolytic metabolism as an effector of signaling. Finally, we observed that inhibiting respiration blocks segmentation and we propose to take advantage of in vitro systems of the developing paraxial mesoderm that we have developed to analyze in depth the role of metabolism in the control of the oscillations of the segmentation clock. This work could shed light on the origin of segmentation defects of the vertebral column such as hemi-vertebrae in humans which have recently been proposed in some cases to be associated to hypoxia acting on the segmentation clock. Our research is expected to have a strong impact in the field of congenital spine anomalies, currently an understudied biomedical area, and will be of utility in elucidating the etiology and eventual prevention of these disorders.
We propose to characterize a specific metabolic state highly reminiscent of the physiology of cancer cells (aerobic glycolysis or Warburg effect) that we identified in the precursors of muscles and vertebrae. Our work is expected to shed light on the origin of this peculiar metabolism in cancer cells and will also help understand the cause of vertebral column defects in diseases such as congenital scoliosis.
| Oginuma, Masayuki; Moncuquet, Philippe; Xiong, Fengzhu et al. (2017) A Gradient of Glycolytic Activity Coordinates FGF and Wnt Signaling during Elongation of the Body Axis in Amniote Embryos. Dev Cell 40:342-353.e10 |
| Hubaud, Alexis; Regev, Ido; Mahadevan, L et al. (2017) Excitable Dynamics and Yap-Dependent Mechanical Cues Drive the Segmentation Clock. Cell 171:668-682.e11 |
