Ivan Juarez

Background: Osteosarcoma is a rare and aggressive primary malignant bone tumor that is most often seen in children, adolescents, and young adults.¹ Metastasis to the lungs remains the leading cause of treatment failure and death, and outcomes for metastatic cases remain poor despite the improvement in localized osteosarcoma.^2,3 Current diagnosis relies on imaging and biopsy, with treatment combining chemotherapy with surgical resection. Many patients are thought to have micrometastatic disease at presentation that goes unseen on imaging, leading to poor outcomes.²  Although osteosarcoma often has genetic abnormalities, including TP53 and RB1 disruption and changes in pathways like Wnt, Notch, and receptor kinase signaling, these mutations do not solely explain why some tumors metastasize and others remain localized.⁴ This review analyzes whether disrupted osteoblast lineage chromatin programs aid in metastatic potential, invasion, and lung colonization.

Objective: The purpose of this review was to analyze how epigenetic regulation aids in osteosarcoma metastasis and how chromatin states may eventually guide prognosis and treatment selection.

Search Methods: A PubMed search was conducted for articles published from 2018 to 2026 using the keywords “osteosarcoma,” “metastasis,” and “epigenetic regulation.”

Results: Recent studies support the idea that metastatic potential may be epigenetically primed before dissemination. Singh et al. used H3K27ac ChIP-seq, ATAC-seq, and RNA-seq in primary osteosarcoma samples and found that tumors from patients who later developed metastases showed a unique, active chromatin profile in comparison to those that remained localized.³ Enhancer activation was associated with altered expression of nearby genes that are associated with invasion and migration including PREX1, PPP1R1B, and IGF2BP1. PREX1 knockdown reduced proliferation, migration, invasion, and colony formation, supporting the idea that PREX1 may have a role as a downstream effector of a pro-metastatic chromatin state.³ Mechanistic studies further identified RepID as a chromatin-associated regulator of osteosarcoma invasion. Jung et al. showed that RepID promotes PRC1-mediated H2AK119 ubiquitination at the GATA6 promoter, acting as a GATA6 expression repressor.⁵ RepID knockout restored GATA6 expression and reduced migration and invasion in transwell/Matrigel assays, linking chromatin repression to an invasive phenotype.⁵ Epigenetic regulation also seems to be important after migration. Pontius et al. found that early and late lung-colonizing osteosarcoma cells develop distinct chromatin accessibility and transcriptional states suggesting that continued adaptation is needed for lung colonization.⁶ López-Fuentes et al. identified early and late osteoblast-derived states with unique chromatin programs that can coexist within patient-derived xenografts and demonstrated different therapeutic sensitivities.⁷ These findings suggest that osteosarcoma cells might have flexible epigenetic states that influence both metastatic adaptation and response to treatment. This is supported clinically by evidence that low H3K27me3 is associated with poor chemotherapy response, showing the potential value of histone modification profiling.⁸

Conclusion: Osteosarcoma metastasis may involve epigenetic priming in the primary tumor, chromatin-driven invasion, and adaptation to the lung microenvironment during colonization. These findings suggest that epigenetic profiling may improve metastatic risk assessment and help in identifying chromatin-associated biomarkers or therapeutic targets. Future studies should investigate and define which epigenetic dependencies may be targeted in patients with high-risk or metastatic osteosarcoma.

Works Cited:

1. Brar GS, Schmidt AA, Willams LR, Wakefield MR, Fang Y. Osteosarcoma: current insights and advances. Exploration of Targeted Anti-tumor Therapy. 2025;6doi:10.37349/etat.2025.1002324
2. Sheng G, Gao Y, Yang Y, Wu H. Osteosarcoma and Metastasis. Frontiers in Oncology. 2021;11doi:10.3389/fonc.2021.780264
3. Singh I, Rainusso N, Kurenbekova L, et al. Intrinsic Epigenetic State of Primary Osteosarcoma Drives Metastasis. Molecular Cancer Research. 2024;22(9):864-878. doi:10.1158/1541-7786.mcr-23-0055
4. Beird HC, Bielack SS, Flanagan AM, et al. Osteosarcoma. Nature Reviews Disease Primers. 2022;8(1)doi:10.1038/s41572-022-00409-y
5. Jung DH, Park JU, Jo JH, et al. RepID promotes metastatic potential in osteosarcoma through regulation of the PRC1-GATA6 axis. Anim Cells Syst (Seoul). 2026;30(1):47-58. doi:10.1080/19768354.2025.2598973
6. Pontius WD, Hong ES, Faber ZJ, et al. Temporal chromatin accessibility changes define transcriptional states essential for osteosarcoma metastasis. Nature Communications. 2023;14(1)doi:10.1038/s41467-023-42656-x
7. López-Fuentes E, Clugston AS, Lee AG, et al. Epigenetic and Transcriptional Programs Define Osteosarcoma Subtypes and Establish Targetable Vulnerabilities. Cancer Discov. Feb 6 2026;16(2):296-319. doi:10.1158/2159-8290.Cd-25-0237
8. Kondratowski S, Cohen D, Deyell RJ, Sandhu A, Bush JW. Immunohistochemical study of histone protein 3 modification in pediatric osteosarcoma identifies reduced H3K27me3 as a marker of poor treatment response. PLOS ONE. 2024;19(11):e0309471. doi:10.1371/journal.pone.0309471