Bone is a frequent site of metastases and many existing therapies are ineffective at metastatic bone sites. Accumulating evidences suggest that bone marrow (BM) microenvironment act as a regulator of cancer cells homing to bone and bone metastasis outgrowth. Inhibition of cancer cells/microenvironment crosstalk represent underexplored potential treatment for bone metastasis.
Adipocytes (BM-Ads) are a major component of the BM microenvironment since they occupy 70% of the total volume of adult BM. These cells are unique in the BM microenvironment due to their secretory and metabolic specificities.
Until now, studying the crosstalk between BM-Ads and tumor cells was clearly hampered by the limited data concerning BM-Ad phenotype in humans and the lack of adequate models for in vitro studies. Thus, we performed the first metabolic characterization of human BM-Ads using a combination of proteomic and lipidomic approaches in collaboration with orthopedic surgeons of Toulouse’s University Hospital (Attané et al, Cell Reports, 2020). We found that BM-Ads morphologically resemble paired subcutaneous adipocytes (SC-Ads; used as a control) but display distinct lipid metabolic features. Our results showed that BM-Ads i) are devoid of lipolytic function, due to a profound down-regulation of MGLL (monoacylglycerol lipase), a lipase involved in the last step of the lipolysis pathway and ii) exhibit a cholesterol-orientated metabolism due to an enrichment in proteins involved in cholesterol synthesis, transport and hydrolysis as well as metabolization into oxysterols. Therefore, our results explain for the first time, at cellular and molecular levels, why BM-Ads behave like a preserved lipid source under caloric restriction.
We have also demonstrated recently that BM-Ads might favor the homing of CCR3 expressing prostate cancer (PCa) cells through their ability to secrete the CCL7 chemokine (Guerard et al, International Journal of Molecular Sciences, 2021). Interesting the CCR3/CCL7 axis is also involved in local PCa invasion in a process dependent of the secretion of mature adipocytes from the periprostatic adipose tissue (Laurent et al, Nature Communications, 2016). The implication of CCR3 in both local and distant invasion of PCa highlights the interest of use of CCR3 inhibitors in PCa.
Our current project aims to decipher the role and nature of the metabolic cross talk between PCa cells and BM-Ads in bone metastasis outgrowth in order to propose innovative drug targets for the treatment of PCa bone metastases. This project has been funded in 2020 by the French National Cancer Institute and is also supported by the Ligue Nationale contre le Cancer.
Other staff involved:
Catherine Muller(Team Leader), Sauyeun Shin (post-doc, fellow of the National Cancer Institute), Marine Hernandez (Master Student in Oncology), Mohammed Moutahir (Technician, CNRS)
- Attané C*, Estève D*, et al. Human Bone Marrow Is Comprised of Adipocytes with Specific Lipid Metabolism Cell Rep 2020 Jan 28;30(4):949-958.e6. doi: 10.1016/j.celrep.2019.12.089.
- Guérard et al. The chemokine receptor CCR3 is potentially involved in the homing of prostate cancer cells to bone : implication of bone -marrow adipocytes. Int. J. Mol. Sci. 2021, 22(4), 1994; https://doi.org/10.3390/ijms22041994.
- Nicolas Reina (Orthopedic surgery unit, Toulouse hospital)
- Jean-Charles Portais and Justine Bertrand-Michel (Toulouse Metabolomic and lipidomic Platform)
- Marc Poirot’s team (CRCT, Toulouse)
- Philippe Valet and Cédric Dray team (Restore Institute, Toulouse)