Temporal chromatin accessibility changes define transcriptional states essential for osteosarcoma metastasis

W. Dean Pontius (), Ellen S. Hong, Zachary J. Faber, Jeremy Gray, Craig D. Peacock, Ian Bayles, Katreya Lovrenert, Diana H. Chin, Berkley E. Gryder, Cynthia F. Bartels and Peter C. Scacheri ()
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W. Dean Pontius: Case Western Reserve University School of Medicine
Ellen S. Hong: Case Western Reserve University School of Medicine
Zachary J. Faber: Case Western Reserve University School of Medicine
Jeremy Gray: Case Western Reserve University School of Medicine
Craig D. Peacock: Case Western Reserve University School of Medicine
Ian Bayles: Case Western Reserve University School of Medicine
Katreya Lovrenert: Case Western Reserve University School of Medicine
Diana H. Chin: Case Western Reserve University School of Medicine
Berkley E. Gryder: Case Western Reserve University School of Medicine
Cynthia F. Bartels: Case Western Reserve University School of Medicine
Peter C. Scacheri: Case Western Reserve University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The metastasis-invasion cascade describes the series of steps required for a cancer cell to successfully spread from its primary tumor and ultimately grow within a secondary organ. Despite metastasis being a dynamic, multistep process, most omics studies to date have focused on comparing primary tumors to the metastatic deposits that define end-stage disease. This static approach means we lack information about the genomic and epigenomic changes that occur during the majority of tumor progression. One particularly understudied phase of tumor progression is metastatic colonization, during which cells must adapt to the new microenvironment of the secondary organ. Through temporal profiling of chromatin accessibility and gene expression in vivo, we identify dynamic changes in the epigenome that occur as osteosarcoma tumors form and grow within the lung microenvironment. Furthermore, we show through paired in vivo and in vitro CRISPR drop-out screens and pharmacological validation that the upstream transcription factors represent a class of metastasis-specific dependency genes. While current models depict lung colonization as a discrete step within the metastatic cascade, our study shows it is a defined trajectory through multiple epigenetic states, revealing new therapeutic opportunities undetectable with standard approaches.

Date: 2023
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DOI: 10.1038/s41467-023-42656-x

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