Epigenetics uncovers new secrets of osteosarcoma

Researchers reveal epigenetic mechanisms involved in bone cancer that could improve prognosis and guide the development of new treatments for tumours resistant to chemotherapy

While clinical trials are a crucial step in developing new cancer treatments, fundamental research is equally essential to identify new therapeutic targets—molecules or cellular structures involved in the development or progression of cancer that can be blocked or modified by drugs. This is especially true in the case of osteosarcoma, the most common form of bone cancer, which primarily affects adolescents and for which survival rates have remained stagnant since the 1990s.

In connection with Québec Sarcoma Day on September 19, researchers at the Research Institute of the McGill University Health Centre (The Institute) are highlighting major advances recently published in Nature Communications. The study uncovers new pathological mechanisms specific to osteosarcoma and points to potential therapeutic avenues. These discoveries are the result of a collaborative effort led by Livia Garzia, PhD, a scientist in the Cancer Research Program at The Institute, together with Nada Jabado, MD, PhD, also a scientist at The Institute, and Claudia Kleinman, PhD, a researcher at the Lady Davis Institute.

“There is an urgent need to develop new treatments for osteosarcoma, because many tumours either come back or become resistant to therapy, and patient survival rates have not improved in the past 35 years. Current treatment protocols still rely on high-dose toxic chemotherapy, something we hope to change through our research,” explains Wajih Jawhar, co–first author of the study and a doctoral student supervised by Prof. Garzia and Dr. Jabado at The Institute.

Unlike some cancers that display clear and recurring genetic mutations, osteosarcoma does not show a consistent genetic pattern. Its main feature is instead a highly disorganized and unstable genome. Since epigenetic disruptions have been identified as a common hallmark of many cancers in children and young adults, researchers turned their attention to the epigenome of bone tumours. In other words, they set out to uncover the chemical modifications that regulate how tumour genes are switched on or off—without altering the DNA itself.

Like a car without brakes: understanding the mechanics to fix it

By studying tumour tissue from two independent patient cohorts, the researchers discovered that about 20% of osteosarcomas show abnormal activation of the gene that produces the EZHIP protein—a protein that is normally absent in bone tissue. This is the first study, across all types of cancer, to provide experimental evidence that EZHIP acts like an oncogene, driving the aggressiveness of the tumour.

The researchers also found that the expression of the EZHIP protein is accompanied by the loss of an epigenetic mark, known as H3K27me3, on a histone protein. This mark normally acts like a ‘brake’ on certain genes. Without this brake, genes that should remain silent become active, leading to uncontrolled cell growth, blocking their differentiation (they remain “immature”), and ultimately driving the formation and persistence of tumours.

In addition, they observed this loss of the histone mark H3K27me3 in some osteosarcomas where the EZHIP protein was not expressed, suggesting that other mechanisms may be at play. Overall, their findings show that either EZHIP expression or the loss of H3K27me3 occurs in about 40% of tumours.

The researchers also showed that low levels of H3K27me3 are more common in tumours that respond less effectively to chemotherapy given before surgery. The presence (or absence) of this epigenetic mark in a patient’s tumour could therefore help doctors predict how well it will respond to chemotherapy and guide them in choosing more appropriate treatments.

Importantly, the team identified a potential therapeutic strategy: tazemetostat. This is an FDA-approved drug with a favourable safety profile that has shown promising results in cellular models expressing the EZHIP protein.

This work is a true collaborative effort between co–first authors Wajih Jawhar, Geoffroy Danieau, PhD (supervised by Prof. Garzia), and Alva Annett, a doctoral student (co-supervised by Prof. Kleinman and Dr. Jabado), who contributed their unique and complementary expertise in sarcoma biology and omics approaches. While the findings open promising avenues for new treatments, more time and research will be needed before they can be applied to patients.

Some facts about osteosarcoma

• Osteosarcoma is a bone cancer that can spread to nearby tissues and form metastases in other parts of the body, often in the lungs. It is debilitating and often fatal.
• Osteosarcoma occurs mainly in children, adolescents, and young adults, with higher incidence rates during puberty and a second peak around the age of 70.
• It can appear in any bone, but is most often found in the leg (femur or tibia) or the arm (humerus). In older adults, it can also be detected in the bones of the pelvis, jaw, or spine.
• Common symptoms include pain, swelling or a lump, and loss of joint mobility.
• Treatment for osteosarcoma usually involves neoadjuvant chemotherapy, surgery, and further chemotherapy. In some cases, amputation is necessary.
• To date, very few risk factors have been identified, and no genetic mutation common to all cases has been found, making it difficult to develop targeted treatments.

Did you know?

Dr. Nada Jabado’s laboratory at The Institute was the first to identify a new molecular mechanism involved in human disease: histone mutations. This discovery paved the way for new personalized therapeutic options that are improving the lives of many children with cancer.

About the study

Aberrant EZHIP expression drives tumorigenesis in osteosarcoma, was authored by Wajih Jawhar, Geoffroy Danieau, Alva Annett, Takeaki Ishii, Andrea Bajic, Ana Castillo-Orozco, Brian Krug, Yara Faucher-Jabado, Justin Seyedmoomenkashi, Mostafa Saquib, Masoumeh Aghababazadeh, Marjan Khatami, Nadim Tawil, Damien Faury, Sungmi Jung, Ahmed Aoude, Robert E. Turcotte, Benjamin Ellezam, Thomas Sontag, Sylvie Langlois, Daniel Sinnett, Swneke D. Bailey, Lingxin Zhang, Dorothée Dal Soglio, Claudia L. Kleinman, Nada Jabado and Livia Garzia

Nature Communications volume 16, Article number: 6752 (2025)

DOI : https://doi.org/10.1038/s41467-025-61558-8

The researchers thank the many organizations and foundations that supported this work, including the Nicole and François Angers Sarcoma Research Fund, the Montreal General Hospital Foundation, the Cedars Cancer Foundation, the Terry Fox Foundation, Génome Québec, Genome Canada, the Government of Canada, the Ministère de l’Économie et de l’Innovation du Québec, the Ontario Research Fund, the Fondation Charles-Bruneau, the National Institutes of Health, the Canadian Institutes of Health Research, the Canadian Cancer Society, the Fonds de recherche du Québec, the CFI Leaders Opportunity Fund, the Uehara Memorial Foundation Fellowship, the McGill Genome Centre, Compute Canada, and Calcul Québec.