{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:22:16Z","timestamp":1791490936397,"version":"4.3.4"},"reference-count":94,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T00:00:00Z","timestamp":1610668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["21403"],"award-info":[{"award-number":["21403"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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-\u0138B 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 \u00b1 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.<\/jats:p>","DOI":"10.3390\/cancers13020311","type":"journal-article","created":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T05:17:34Z","timestamp":1610947054000},"page":"311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8151-8105","authenticated-orcid":false,"given":"Margherita","family":"Cortini","sequence":"first","affiliation":[{"name":"Biomedical Science and Technology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Armirotti","sequence":"additional","affiliation":[{"name":"Analytical Chemistry Lab, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Columbaro","sequence":"additional","affiliation":[{"name":"Biomedical Science and Technology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6906-9925","authenticated-orcid":false,"given":"Dario Livio","family":"Longo","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council of Italy, 10135 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5121-4330","authenticated-orcid":false,"given":"Gemma","family":"Di Pompo","sequence":"additional","affiliation":[{"name":"Biomedical Science and Technology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cannas","sequence":"additional","affiliation":[{"name":"Analytical Chemistry Lab, Fondazione Istituto Italiano di Tecnologia, 16163 Genova, Italy"},{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum-Universit\u00e0 di Bologna, 40125 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Maresca","sequence":"additional","affiliation":[{"name":"Programma di Neurogenetica, IRCCS Istituto Delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4504-2867","authenticated-orcid":false,"given":"Costantino","family":"Errani","sequence":"additional","affiliation":[{"name":"Oncologic Orthopaedic Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6708-3777","authenticated-orcid":false,"given":"Alessandra","family":"Longhi","sequence":"additional","affiliation":[{"name":"Chemotherapy Unit for Musculoskeletal Tumors, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Righi","sequence":"additional","affiliation":[{"name":"Anatomy and Pathological Histology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Carelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum-Universit\u00e0 di Bologna, 40125 Bologna, Italy"},{"name":"Programma di Neurogenetica, IRCCS Istituto Delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Baldini","sequence":"additional","affiliation":[{"name":"Biomedical Science and Technology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"},{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum-Universit\u00e0 di Bologna, 40125 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-0591","authenticated-orcid":false,"given":"Sofia","family":"Avnet","sequence":"additional","affiliation":[{"name":"Biomedical Science and Technology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"},{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum-Universit\u00e0 di Bologna, 40125 Bologna, 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