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Redefining Osteosarcoma Metastases as Chronic Non-healing Lung Wounds: Implications for Developing Novel Therapies

Institution: 
Research Institute at Nationwide Children's Hospital
Researcher(s): 
James Reinecke, MD/PhD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2021
Type of Childhood Cancer: 
Osteosarcoma
Project Description: 

Osteosarcoma is a bone cancer that affects children, adolescents, and young adults. Thanks to modern treatment approaches, nearly 7 out of 10 young people diagnosed with osteosarcoma survive into adulthood. Unfortunately, a significant number of patients die from osteosarcoma, most often because the osteosarcoma cells have spread to areas outside of the bone through a process called metastasis. When some cancers metastasize, they go to multiple organs throughout the body. Osteosarcoma is unique in that it largely metastasizes only to the lung. Once osteosarcoma starts to grow in the lung, there are no effective treatments to stop them from growing, which eventually leads to death. My research focuses on understanding why osteosarcoma "prefers" the lung, how osteosarcoma changes the lung to suite its needs, and how altered lung cells promote osteosarcoma survival in the lung. My work demonstrates that osteosarcoma cells induce a “scab” or wound within the lung. While most wounds heal without incident, my work demonstrates that osteosarcoma cells trick the lung into thinking there is constant injury. The lung reacts to this by depositing proteins and other factors that allow the osteosarcoma cells to survive and grow within the lung. This proposal aims to figure out how osteosarcoma cells induce this wound environment in order to find drugs that can stop the process, which would inhibit osteosarcoma growth within the lung. Therapies that prevent or treat lung metastasis could save 80% of lives lost to osteosarcoma.

Project Goal:

The long-term goal of this Alex Lemonade Stand Young Investigator proposal is to discover therapies that are effective against osteosarcoma metastasis. The short-term goals of this proposal are to address the following three questions: 1) How do osteosarcoma cells change cells within the lung? 2) How do altered lung cells help osteosarcoma cells survive in the lung? and 3) How do cells that surround and support osteosarcoma cells change over time? My proposal will address each of these related questions using state-of-the art technologies.

Project Update 2024:

Osteosarcoma metastasis is as deadly now as it was 40 years ago because 30-40% of patients will develop lung metastasis. My work has demonstrated that when osteosarcoma cells colonize the lung, they make they lung think it is "wounded". The osteosarcoma wound cannot heal, and the lungs response to that promotes osteosarcoma metastasis. During the first year of my ALSF-YI, I focused on understanding why the induction of a non-healing wound in the lung promotes osteosarcoma metastasis. I have found that epithelial cells, which are normal cells found in the lung, induce osteosarcoma cells to produce a matrix. This matrix surrounds the osteosarcoma cells and protects them from chemotherapy. Inhibiting this matrix restores chemotherapy sensitivity. Lastly, as a proof of principle, we performed pre-clinical trials (in mice) using a drug that is used for patients who don't have cancer but have diseases that cause non-healing wounds in the lung. This medication caused a striking reduction in metastasis. Through generous support from ALSF/Northwestern Mutual, I will be exploring if this drug can be combined with immunotherapy or conventional chemotherapy to reduce metastasis.

Final Project Update 2025:

My work supported through this award provided the protected time required to understand and harness preclinical models towards understanding the complex biology of metastasis. My project focused on understanding how osteosarcoma, a bone tumor that impacts children, adolescent and young adults, spreads or metastasizes to the lung. Lung metastasis is the cause of nearly all deaths related to osteosarcoma, underscoring the urgent need for developing new therapies that can effectively disrupt metastasis. My work found that osteosarcoma cells transform the affected parts of the lung into a chronic wound (think of a scab the continues to be picked at and opened). Osteosarcoma cells generate this chronic wound through interacting with normal lung cells (epithelial cells). Importantly, we found that disrupting communication between osteosarcoma cells and lung epithelial cells, or blocking the abnormal wound healing process initiated by osteosarcoma cells in the lung, prevents metastasis growth in mouse models of osteosarcoma. In total, my ALSF work demonstrated that the interactions between cancer cells and normal cells are critical in metastasis, but most importantly, provide potential targets to disrupt the metastatic process. I will be using the conceptual tools learned during this project as I transition to independence, as a neuro-oncologist focused on understanding leptomeningeal metastasis in pediatric brain tumors.

Co-funded by: 
Northwestern Mutual Foundation

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