LLNL scientists use engineered bone marrow for cancer research and treatment

Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. While many other cancers now have promising therapeutic advances, treatment options for OS have remained unchanged since the introduction of standard chemotherapeutics and offer less than a 25% five-year survival rate for those with metastatic disease.

Now, Lawrence Livermore National Laboratory (LLNL) scientists along with collaborators from the University of California, Davis and the UC Davis Comprehensive Cancer Center have adapted previously described engineered bone marrow (eBM) for use as a 3D platform to study how microenvironmental and immune factors affect OS tumor progression.

The research highlights the applicability of eBM as a drug-screening platform and shows that eBM offers a protective effect on OS cells that parallel clinical responses and could increase the survival rate of OS patients.

The treatment of OS and improvement of disease outcome has seen limited clinical progress due to a lack of understanding regarding primary and metastatic OS pathophysiology. Such improvements require improved understanding of the events leading from early OS development in the bone marrow to preferential pulmonary metastasis, yet limited models exist to investigate these events.

“eBM is an exciting platform that provides a significant advancement to in vitro primary bone tumor research, as well as biomaterial tissue engineering at large,” said J. Kent Leach of the UC Davis Department of Orthopaedic Surgery and lead author of a paper appearing in the Proceedings of the National Academy of Sciences. “Within the context of cancer, eBM has the potential to be used to study newly identified cancer targets, complex immune cell-cancer interactions and metastagenesis biology, both as it relates to primary sarcoma metastasis away from bone and metastatic carcinoma to the bone.”

The eBM in this project accounts for the diverse cell population, complex cytokine assortment and 3D components of OS, surpassing previous in vitro models that do not account for the combined effects of these key parameters. The team demonstrated how eBM can be used in basic science research to study primary tumor formation, as well as its translational applications as a drug screening platform.

“We show that eBM stably recapitulates the composition of native bone marrow,” said LLNL scientist and co-author of the paper Nicholas Hum. “OS cells exhibit differential behavior dependent on metastatic potential when cultured in eBM, thus mimicking in vivo conditions.”

The team implanted eBM on acellular bone-forming materials in mice and removed the cellularized constructs after eight weeks for study. Team members then looked at the influence of the anatomical implantation site on eBM tissue quality, tested ex vivo stability under different culture conditions, cultured OS cells within these constructs and compared them to human OS samples.

“This work presents eBM as a cellular construct that mimics the complex bone marrow environment that is useful for mechanistic bone cancer research and drug screening,” said LLNL scientist Aimy Sebastian, a co-author of the study.

LLNL scientist Gabriela Loots also contributed to this research. The work is funded by the UC Davis School of Veterinary Medicine Endowment Funds and Graduate Student Support Program, the Musculoskeletal Tumor Society Mentored Research Award Project and the UC Davis Comprehensive Cancer Center.