Bioengineered Bone Marrow Model Reveals Potential New Strategies for Osteosarcoma Metastasis Control

R. Lor Randall, MD, FACS

Immune system manipulation can regulate osteosarcoma behavior—including the disease’s metastatic potential—indicating the potential for a future of sarcoma management where metastatic phenotypes could be reverted to nonmetastatic states, thereby increasing patients’ eligibility for localized treatment, according to R. Lor Randall, MD, FACS.

In a paper published in Biomaterials Advances in 2025, Randall and colleagues presented findings from a study that used models of the hematological bone marrow environment designed to mimic the native osteosarcoma tumor environment. This study showed that osteosarcoma’s oxygen tension sensitivity increases when the disease is cultured 3-dimensionally. Additionally, differing osteosarcoma responses to macrophages were associated with the disease’s metastatic potential.

“We now have a model where we can evaluate macrophage and immunocompetent interleukin factors and ways by which we can manipulate those to understand osteosarcoma, which we haven’t been able to do until now because [our research was limited to] immunocompromised mice,” Randall said in an interview with OncLive®.

In the interview, Randall discussed the challenges associated with treating patients with osteosarcoma, the importance of the development of this bioengineered bone marrow matrix to study this disease, the model’s mechanisms of oxygen tension manipulation and macrophage polarization for potential metastasis control, and how this model could aid in the investigation of new therapeutic strategies for patients with both bone and soft tissue sarcomas.

Randall is the David Linn Endowed Chair for Orthopaedic Surgery, as well as the chair of and a professor in the Department of Orthopaedic Surgery at the University of California Davis in Sacramento.

OncLive: What was the rationale for investigating the immunomodulatory relationship between osteosarcoma and macrophages?

Randall: Osteosarcoma is the most common form of bone cancer in adolescents and young adults. The most common form of bone cancer overall is chondrosarcoma, but osteosarcoma [is the most common bone cancer] in younger patients. Both medical and pediatric oncologists treat these patients. In the past 50 years, no new therapies have been

developed. In the cancer therapeutic paradigm across all the different tumors, immunotherapies and a variety of other treatments have been developed that have moved the needle in managing other forms of cancer.

However, although osteosarcoma has smart, passionate investigators and scientists working on [treatment developments], and we’ve made no major inroads. Most of the osteosarcoma models that have been produced have been in immunocompromised mice. If we’ve learned one thing in cancer biology in the past decade or so, it is that the immune system matters. [With the use of] CAR T-cell therapies or just conventional therapies, the immune system influences the journey of the patient with cancer because [their treatment has an] interplay [with whether the immune system] is being targeted.

However, we haven’t been able to investigate the immune system much in osteosarcoma. In other translocation-derived sarcomas, we can form—with good fidelity—a model of a sarcoma in a genetically engineered mouse with a competent immune system. However, the osteosarcoma genome is shattered. There’s no rhyme or reason to the initiating events. We allude to stem cell biology and a variety of other [causes], but we [have not been able to] create an immunocompetent model. That becomes a challenge. Many of us then have reverted to petri dish, in vitro work, and we know the limits there.

[I was a coauthor on a paper published in 2023] in the Proceedings of the National Academy of Sciences investigating a bioengineered bone marrow matrix for studying osteosarcoma. We’ve followed up with that research, investigating different types of osteosarcoma cell lines in this engineered 3-dimensional space. We evaluated the way that oxygen tension and macrophages interface with the progression of osteosarcoma.

This paper that was published in Biomaterials Advances is technical. However, it’s fair to say that when you introduce a metastatic phenotype into the bone marrow, [changing the phenotype from nonmetastatic to metastatic], and you manipulate the oxygen tension and the macrophage polarization in the immunoenvironment, you can get different responses of those cells. At this point, that finding has no direct therapeutic implications, but now we have a model by which we can manipulate the immune system and see how it affects osteosarcoma pathology.

What were the key findings from this research, and how might they influence clinical practice in the future?

This model has cell lines that are nonmetastatic and cell lines that are metastatic that we have put into engineered bone marrow. We can manipulate the oxygen tension and polarize the macrophages, which are drivers for inflammation, as well as drivers for oncogenesis with M1 and M2 polarization. We can manipulate those [macrophages] and evaluate the signatures of the metastatic and nonmetastatic cell lines to see whether the nonmetastatic lines change [based on] the signature of the metastatic phenotype.

[This will reveal whether there] are certain events that we can revert to the metastatic or nonmetastatic phenotype by manipulating those environments [and therefore] potentially control the metastasis, which is the [goal]. Once we understand whether [metastasis is caused by] oxygen tension or macrophage polarization, there are drugs that can be used to manipulate those environments to potentially revert [the cancer’s] metastatic phenotype to nonmetastatic. The implication could be that if [a patient has] metastases in the lung, [for example], we can change the microenvironment there such that those cells become less aggressive, and then we could potentially treat [these patients] with surgery to [resect their disease] because it is no longer metastatic.

Could other sarcoma types beyond osteosarcoma benefit from this type of modeling?

[That is] what we would like to [investigate]. In all the pleomorphic, shattered-genome soft tissue sarcomas that don’t have a defined translocation or molecular inciting event, [we want to] do the same thing with the microenvironment. [We want to] put [these tumors] into a connective tissue environment where cells are metastatic or nonmetastatic and manipulate those trigger points to see whether we can revert the metastatic phenotype to the nonmetastatic phenotype.

This is a theoretical discussion [based on] a technical paper, but hopefully, it will incite thoughts of ways by which we can approach cancer [management], not just to try to cure patients, but to push it into a chronic disease state. Wouldn’t it be exciting, too, if we could reverse phenotypes from metastatic to nonmetastatic?

Reference

Griffin KH, Sagheb IS, Coonan TP, et al. Macrophage and osteosarcoma cell crosstalk is dependent on oxygen tension and 3D culture. Biomater Adv. Published online December 16, 2024. doi:10.1016/j.bioadv.2024.214154