This observation potentially explains why current immunotherapy agents in the clinic lack efficacy in OS. Our ongoing research builds upon recent discoveries indicating that RUNX2, together with its chromatin-binding partners, regulates immune-related genes. John Bushweller’s group at UVA to test the effect of CBFB inhibitors in killing osteosarcoma cells. For example, we are collaborating with Dr. This early stage of investigation has yielded several molecular targets for OS. (He et al, Stem Cell Reports, 2017).Ĥ) SOX9 is a key component of the RUNX2 transcriptional circuitry in OS, acting both a downstream target of RUNX2 and a partner to induce MYC expression. For example, SOX9 mediates the development of chondroblastic OS. (Shin et al., PLOS Genetics, 2016).ģ) Several transcription factors determine the lineage choice of OS development from MSCs. (He et al., Stem Cells, 2015).Ģ) The CBFB-RUNX2 complex is essential for osteosarcoma cell survival as it recruits the Menin/MLL complex to epigenetically induce MYC expression. Our previous research generated insights into the functional interactions between these transcription factors, described as follows.ġ) p53 represses RUNX2 via microRNA 34s, a regulation critical for the osteoblast differentiation of mesenchymal stem cells (MSCs). Our objective is to elucidate a comprehensive depiction of the core regulatory network in OS. As these genes encode transcription factors, we posit that transcriptional dysregulation serves as a key factor in driving osteosarcoma progression. Genomic and epigenomic studies have uncovered the prevalence of RUNX2 and/or MYC amplification in addition to TP53 deletion or mutation in many osteosarcoma (OS) tumors. Presently, there is a lack of FDA-approved targeted therapies for OS, and immunotherapies, including anti-PD-L1, have proven ineffective in clinical trials. The development of new therapies for OS poses significant challenges. Osteosarcoma (OS) stands as the second leading cause of cancer-related death in children and young adults, with its standard care remaining unchanged for the past four decades. Project 1: Transcriptional and epigenetic vulnerabilities in osteosarcoma. Our goal is to use this knowledge to develop new treatments for these cancers in the future. Currently, we are investigating transcription factors that drive osteosarcoma and breast cancer, identifying key players like RUNX2, RUNX1, CBFB, and SOX9. In previous studies, we explored the role of p53 in stress responses of embryonic stem cells, uncovering insights into how these cells maintain their genetic stability. Our research aims to understand how gene expression is regulated in cancer cells and stem cells.
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