Researchers show that restoring adenosine deaminase acting on RNA 2 activity forces osteosarcoma cells to differentiate and become less aggressive

Osteosarcoma is the most common primary bone cancer in children, adolescents, and young adults. Although chemotherapy and surgery have improved survival for localized disease, outcomes remain poor when tumors spread to the lungs or return after treatment. A major challenge is that osteosarcoma cells often remain locked in an immature developmental state, allowing them to grow rapidly and invade surrounding tissues. Thus, it is necessary to identify and develop new therapeutic targets and strategies.

To address this challenge, a research team led by Dr. Andrea Del Fattore, Head of the Bone Physiopathology Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy and Prof. Angela Gallo from the Unit of Genetic and Epigenetics of pediatric tumors, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy investigated whether the RNA-editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) could reverse the aggressive behavior of osteosarcoma cells. Using patient datasets, laboratory cell models, transcriptomic analysis, and mouse studies, the researchers examined how restoring ADAR2 affects tumor growth and bone differentiation. Their findings were published in Volume 14 of the journal Bone Research on April 03, 2026.

The team first found that ADAR2 levels naturally rise when healthy mesenchymal stem cells develop into bone-forming osteoblasts. “In contrast, osteosarcoma tissues and highly aggressive cancer cell lines showed markedly reduced ADAR2 expression. Lower ADAR2 levels were also associated with poorer metastasis-free survival and overall survival in patient datasets, suggesting that loss of this enzyme may be linked to more dangerous disease” says Dr. Michela Rossi from the Bone Physiopathology Research Unit, Bambino Gesù Children’s Hospital, first author of the manuscript.

When the researchers increased ADAR2 expression in osteosarcoma cells, tumor-like behavior declined sharply, cell growth slowed, invasive capacity dropped, and migration was reduced. In one osteosarcoma model, the treated cells began producing mineralized matrix, a hallmark of mature bone tissue. Genes linked to osteoblast differentiation increased, while markers associated with stemness and malignancy declined.

“Our findings suggest that osteosarcoma cells are not irreversibly fixed in an aggressive state. By restoring ADAR2, we were able to reactivate developmental programs that steer these cells toward a more mature and less harmful identity,” says Dr.Del Fattore.

The benefits extended beyond cell culture. In mice implanted with human osteosarcoma cells, ADAR2-restored tumors were smaller, less invasive, and less likely to spread to the lungs or liver. Some animals developed minimal tumor burden compared with controls. The treated cells also showed greater sensitivity to methotrexate and selected anti-cancer compounds, indicating that ADAR2-based approaches may strengthen existing therapies rather than replace them.

To understand how ADAR2 exerts these effects, the team analyzed RNA changes across treated cells. They identified insulin-like growth factor binding protein 7 (IGFBP7) as one of the most strongly edited RNA targets. Normally, IGFBP7 can stimulate growth-related IGF signaling pathways that help cancer cells survive and proliferate. However, once edited by ADAR2, this signal was weakened. The edited form no longer promoted proliferation and instead supported expression of bone-development regulators such as runt-related transcription factor 2.

“In my lab, we have studied RNA editing for years, focusing on the role of epitranscriptomic reprogramming in highly aggressive brain tumors. Building on this work and in collaboration with Dr. Del Fattore’s team, we have now demonstrated that ADAR2 also plays a similar tumor-suppressive role in osteosarcoma, opening the way to novel therapeutic targets for this and other tumours. ” says Prof. Gallo.

The findings may have broader ripple effects beyond bone cancer. RNA editing is increasingly implicated in leukemia, brain tumors, and several solid cancers, meaning the study could stimulate collaborations among pediatric oncologists, RNA biologists, and drug developers. Over the next decade, therapies designed to reprogram cancer cells toward maturation could reduce reliance on highly toxic treatment regimens.

Overall, the study provides strong preclinical evidence that restoring ADAR2 can suppress osteosarcoma progression by promoting terminal bone differentiation and weakening metastatic behavior. By targeting the developmental state of cancer cells rather than only destroying them, the research points toward a promising new direction for future pediatric cancer therapy.
Reference
Title of original paper: ADAR2 induces the differentiation of osteosarcoma cells by editing activity on IGFBP7: new implications for therapy
Journal: Bone Research
DOI: 10.1038/s41413-026-00516-6