Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target

SIMPLE SUMMARY: By studying the role of tumor acidosis in osteosarcoma, we have identified a novel lipid signaling pathway that is selectively activated in acid-induced highly metastatic cell subpopulation. Furthermore, when combined to low-serine/glycine diet, the targeting of this acid-induced lipid pathway by the FDA-approved drug FTY720 significantly impaired tumor growth. This new knowledge will provide a giant leap in the understanding of the molecular mechanisms responsible for sarcoma relapses and metastasis. Finally, we paved the way to the recognition of a novel biomarker, as our data provided evidence of significantly high circulating levels in the serum of osteosarcoma patients of S1P, a lipid member of the identified acid-driven metabolic pathway. ABSTRACT: 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.