Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of CALR transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.

Automated summary

Osteosarcoma (OS), a primary bone cancer, can be treated using protein-based therapy derived from mesenchymal stem cells (MSCs). The study discovered that activating PKA can convert MSCs into induced tumor-suppressing cells (iTSCs). Administering a conditioned medium (CM) collected from MSCs inhibited tumor-induced bone destruction and showed synergistic effects with cisplatin in a mouse model. The CM was enriched with proteins like calreticulin and PCOLCE, which acted as extracellular tumor suppressors by interacting with CD47 and amyloid precursor protein respectively.