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-ĸB 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.