Cellular senescence-driven transcriptional reprogramming of the axis activates the pathway and promotes osteosarcoma progression.

Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults. However, a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60. Elderly patients with osteosarcoma exhibit different characteristics compared to young patients, which usually results in a poor prognosis. The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications. Senescent cells can accelerate tumor progression by metabolic reprogramming. Recent research has shown that methylmalonic acid (MMA) was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics. We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells. The expression of was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged. Specifically, we first confirmed a novel molecular mechanism between cellular senescence and cancer, in which the MMA-driven transcriptional reprogramming of the axis accelerated osteosarcoma progression via the activation of pathways. Moreover, the down-regulation of the axis increased the sensitivity and effect of inhibitors in osteosarcoma through significant inhibition of phosphorylation. In conclusion, we confirmed that is a novel age-dependent biomarker for osteosarcoma, and targeting the axis in combination with inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.