Exploring metabolic adaptations to the acidic microenvironment of osteosarcoma cells unveils sphingosine 1-phosphate as a valuable therapeutic target

M. Cortini, A. Armirotti, M. Columbaro, D.L. Longo, G. Di Pompo, E. Cannas, A. Maresca, C. Errani, A. Longhi, A. Righi, V. Carelli, N. Baldini, S. Avnet

Research output: Contribution to journalArticlepeer-review


Acidity is a key player in cancer progression, modelling a microenvironment that prevents immune surveillance and enhances invasiveness, survival, and drug resistance. Here, we demonstrated in spheroids from osteosarcoma cell lines that the exposure to acidosis remarkably caused intracellular lipid droplets accumulation. Lipid accumulation was also detected in sarcoma tissues in close proximity to tumor area that express the acid-related biomarker LAMP2. Acid-induced lipid droplets-accumulation was not functional to a higher energetic request, but rather to cell survival. As a mechanism, we found increased levels of sphingomyelin and secretion of the sphingosine 1- phosphate, and the activation of the associated sphingolipid pathway and the non-canonical NF-κB pathway, respectively. Moreover, decreasing sphingosine 1-phosphate levels (S1P) by FTY720 (Fingolimod) impaired acid-induced tumor survival and migration. As a confirmation of the role of S1P in osteosarcoma, we found S1P high circulating levels (30.8 ± 2.5 nmol/mL, n = 17) in the serum of patients. Finally, when we treated osteosarcoma xenografts with FTY720 combined with low-serine/ glycine diet, both lipid accumulation (as measured by magnetic resonance imaging) and tumor growth were greatly inhibited. For the first time, this study profiles the lipidomic rearrangement of sarcomas under acidic conditions, suggesting the use of anti-S1P strategies in combination with standard chemotherapy. © 2021 by the authors.
Original languageEnglish
Pages (from-to)1-25
Number of pages25
Issue number2
Publication statusPublished - 2021


  • Acidity
  • FTY720
  • Lipidomics
  • Osteosarcoma
  • Sphingolipid
  • Sphingosine 1-phosphate
  • Tumor microenvironment
  • fat droplet
  • fingolimod
  • glycine
  • lysosome associated membrane protein 2
  • serine
  • sphingosine 1 phosphate
  • thermozymocidin
  • acidity
  • acidosis
  • adaptation
  • animal experiment
  • animal model
  • antineoplastic activity
  • Article
  • cancer inhibition
  • cancer recurrence
  • cancer tissue
  • cell migration
  • cell survival
  • clinical article
  • concentration (parameter)
  • controlled study
  • diet restriction
  • drug targeting
  • human
  • human cell
  • human tissue
  • lipid metabolism
  • lipid storage
  • male
  • metastasis
  • mouse
  • nonhuman
  • nuclear magnetic resonance imaging
  • osteosarcoma
  • osteosarcoma cell line
  • protein function
  • tumor microenvironment
  • tumor spheroid


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