Mitochondria as Key Players in Sarcoma Development, Progression and Drug Resistance: From Mechanistic Insights to New Treatment Opportunities

Sarcomas are a heterogeneous group of tumors accounting for 1% and 15% of adult and child cancers, respectively. Because of their high genomic instability, biological heterogeneity and metastatic potential, sarcomas are challenging to treat. Current treatments rely on surgical resection combined with chemotherapy and radiotherapy; however, the outcome remains poor in advanced or recurrent stages. As in many other solid tumors, a growing body of evidence in sarcoma also highlights the central role of metabolic reprogramming in progression and treatment resistance. Mitochondria are key players in bioenergetic processes, redox balance and apoptotic signaling. This review will discuss the latest findings demonstrating that alterations in mitochondrial energetic metabolism, mitochondrial dynamics and mitochondria-dependent pro-apoptotic signaling promote malignant transformation, progression, immune evasion and resistance to treatments in soft-tissue and bone sarcomas. Mitochondrial pleiotropism, however, can unveil new vulnerabilities. Several compounds disrupting mitochondrial respiration, increasing the production of mitochondrial reactive oxygen species, and triggering mitochondrial-dependent apoptosis achieved promising results at a preclinical level as new anti-sarcoma agents, alone or combined with chemotherapy, radiotherapy or immunotherapy. Knowing the multifaceted roles of mitochondria in sarcoma progression and resistance may be the first step toward new treatment tools, noteworthy for future clinical development.