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<p>Li-Fraumeni syndrome (LFS), driven by germline TP53 mutations, confers a markedly elevated risk of osteosarcoma (OS), yet the mechanisms beyond TP53 remain insufficiently defined. By integrating multi-omics analyses and in vitro validation, we identify SCL-interrupting locus (STIL) as a pivotal hub linking LFS to OS progression. We reveal that STIL negatively regulates p53 protein stability in a manner independent of TP53 mutation status, indicating that STIL can promote tumorigenesis by dampening p53 pathway activity and stability. Importantly, STIL displays genetic-context–dependent oncogenicity: it supports stemness across OS models, but more strongly drives invasion and metastatic potential in TP53-mutant backgrounds. Specifically, STIL is highly expressed in a population of high-stemness malignant cells (Pro-OSCs), where it maintains stemness and promotes bone destruction by activating PTN–NCL and FN1–CD44 pathways, while simultaneously remodeling the immune microenvironment via MIF and APP signaling to evade immune surveillance. Additionally, WEE1 inhibitors may represent a targeted vulnerability in STIL-high OS. In summary, the relationship between TP53 and STIL is not a simple linear upstream-downstream cascade, but reflects a highly context-dependent regulatory dynamic. STIL exerts oncogenic effects by regulating p53 stability and driving a “stemness-invasive” phenotype in the context of TP53 mutations. This also provides novel biomarkers and intervention targets for precision therapy.</p>

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Multi-omics analysis reveals the key role of STIL in Li-Fraumeni syndrome and osteosarcoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Yu Qiao,
  • Jincen Hao,
  • Fahu Yuan,
  • Anna Curto-Vilalta,
  • Long Tang,
  • Rüdiger von Eisenhart-Rothe,
  • Florian Hinterwimmer

摘要

Li-Fraumeni syndrome (LFS), driven by germline TP53 mutations, confers a markedly elevated risk of osteosarcoma (OS), yet the mechanisms beyond TP53 remain insufficiently defined. By integrating multi-omics analyses and in vitro validation, we identify SCL-interrupting locus (STIL) as a pivotal hub linking LFS to OS progression. We reveal that STIL negatively regulates p53 protein stability in a manner independent of TP53 mutation status, indicating that STIL can promote tumorigenesis by dampening p53 pathway activity and stability. Importantly, STIL displays genetic-context–dependent oncogenicity: it supports stemness across OS models, but more strongly drives invasion and metastatic potential in TP53-mutant backgrounds. Specifically, STIL is highly expressed in a population of high-stemness malignant cells (Pro-OSCs), where it maintains stemness and promotes bone destruction by activating PTN–NCL and FN1–CD44 pathways, while simultaneously remodeling the immune microenvironment via MIF and APP signaling to evade immune surveillance. Additionally, WEE1 inhibitors may represent a targeted vulnerability in STIL-high OS. In summary, the relationship between TP53 and STIL is not a simple linear upstream-downstream cascade, but reflects a highly context-dependent regulatory dynamic. STIL exerts oncogenic effects by regulating p53 stability and driving a “stemness-invasive” phenotype in the context of TP53 mutations. This also provides novel biomarkers and intervention targets for precision therapy.