Engineered bone marrow as a clinically relevant ex vivo model for primary bone cancer research and drug screening

Journal Article · 19 September 2023 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.2302101120 · OSTI ID:2331530

Griffin, Katherine H.  ^[1]; Thorpe, Steven W. ^[1]; Sebastian, Aimy ^[2]; Hum, Nicholas R. ^[2]; Coonan, Thomas P. ^[1]; Sagheb, Isabel S. ^[1]; Loots, Gabriela G. ^[3]; Randall, R. Lor ^[1]; Leach, J. Kent  ^[1]

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1. University of California, Davis, CA (United States)
2. Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States). Physical and Life Sciences
3. University of California, Davis, CA (United States); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States). Physical and Life Sciences

Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. While numerous other cancers now have promising therapeutic advances, treatment options for OS have remained unchanged since the advent of standard chemotherapeutics and offer less than a 25% 5-y survival rate for those with metastatic disease. This dearth of clinical progress underscores a lack of understanding of OS progression and necessitates the study of this disease in an innovative system. Here, we adapt a previously described engineered bone marrow (eBM) construct for use as a three-dimensional platform to study how microenvironmental and immune factors affect OS tumor progression. We form eBM by implanting acellular bone-forming materials in mice and explanting the cellularized constructs after 8 wk for study. We interrogate the influence of the anatomical implantation site on eBM tissue quality, test ex vivo stability under normoxic (5% O₂) and standard (21% O₂) culture conditions, culture OS cells within these constructs, and compare them to human OS samples. We show that eBM stably recapitulates the composition of native bone marrow. OS cells exhibit differential behavior dependent on metastatic potential when cultured in eBM, thus mimicking in vivo conditions. Furthermore, we highlight the clinical applicability of eBM as a drug-screening platform through doxorubicin treatment and show that eBM confers a protective effect on OS cells that parallel clinical responses. Combined, 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.

• Research Organization: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
• Sponsoring Organization: USDOE National Nuclear Security Administration (NNSA); UC Davis School of Veterinary Medicine Endowment Fund; Musculoskeletal Tumor Society Mentored Research Award; UC Davis Comprehensive Cancer Center; Lawrence J. Ellison Endowed Chair of Musculoskeletal Research
• Grant/Contract Number: AC52-07NA27344
• OSTI ID: 2331530
• Report Number(s): LLNL--JRNL-850896; 1077229
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 39 Vol. 120; ISSN 0027-8424
• Publisher: National Academy of SciencesCopyright Statement
• Country of Publication: United States
• Language: English