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

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.

Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma

“…An acidic pH further drives resident or tumor-recruited MSCs to secrete pro-tumorigenic mediators [24,25]. We have extensively shown that a low pH directly influences OS cell behavior [26][27][28][29][30] and reprograms tumor-associated MSCs into an OS-supporting phenotype. Specifically, a low pH activates the NF-κB inflammatory pathway in MSCs by inducing expression of the RelA proto-oncogene NF-κB subunit (RelA), RelB proto-oncogene NF-κB subunit (RelB), and nuclear factor kappa B subunit 1 (NFKB1), as well as nuclear internalization of the NF-κB complex, which, in turn, activates the transcription of IL6 and IL8.…”

Acid Microenvironment in Bone Sarcomas

“…These pathways can regulate oncogenes or oncometabolites or be involved in the generation of bioactive lipids. In the former case, the RAB39A-RXRB axis has been shown to have a prominent role in the development of osteosarcoma stemness and aggressiveness at a pH of 6.5 [145], while in the latter case, the pH-dependent accumulation of S1P seems to be of paramount importance in the survival and growth potential of osteosarcoma xenografts [82].…”

“…Extracellular acidosis has also been described to influence anticancer immune response and autophagy in a number of solid tumours. However, the role of autophagy in mediating survival to acidosis has not been confirmed in osteosarcoma, where the autophagic flux seems to be unchanged between pH conditions (7.4 and 6.8) [37,82], and the impact of acidosis on the infiltration of inflammatory or immune cells has not been explored thus far. Furthermore, the system by which tumour cells can sense extracellular acidosis has not been deeply investigated yet, but few specific sensors have been identified.…”

“…More recently, evidence has shown that extracellular acidosis, obtained in unbuffered conditions, is also responsible for prominent metabolic plasticity that leads to the accumulation of intracellular lipids, specifically sphingolipids and sphingosine 1-phosphate (S1P). Impairing S1P levels by means of Fingolimod, an FDA-approved drug for the treatment of multiple sclerosis, was of predominant importance to decrease the migration potential of acid-resistant cells, to increase apoptosis, and to impair xenograft growth [82]. This suggests, for the first time, the use of an anticancer drug that has the potential to specifically target the acid-resistant subpopulation in osteosarcoma.…”

Extracellular Acidification Induces Lysosomal Dysregulation

“…One way to reverse and prevent this damage would be to replace these acid sensitive lipids with lipids that are better suited for, or protected from, acid exposure. It has been shown previously that cells adapted to an acidic extracellular environment have increased expression of LAMP2b and increased representation on the plasma membrane [ 13 , 52 , 53 , 54 ]. Due to the acidic nature of the lysosomal lumen, the lipid composition of the inner leaflet of the lysosomal membrane has an increased concentration of lipids that are resistant to acid hydrolysis.…”