Unraveling KLF4 dependency in metastatic osteosarcoma

项目总结 虽然转移是导致90%癌症患者死亡的原因，但大多数靶向治疗都是已经开发出来的。 根据原发肿瘤的生物学特征。这种差异突出了临床上迫切需要更好地 了解是什么赋予癌症在新的微环境中定居和茁壮成长的能力。为 骨肉瘤(OS)，尽管几乎所有患者都表现出 某种程度的转移性负担。我们实验室最近的研究已经证明了OS的过程 肺转移是由增强子格局的改变驱动的。肿瘤转移特异性变异增强基因座 (MET-Vel)是无处不在的，并调节对这种肺内原发骨癌生长至关重要的基因。 然而，OS的异质性限制了这些发现的临床翻译。一个统一的分子 因此，与转移相关的增强子重塑的上游机制将提供新的结节 用于治疗靶向。将全面增强子分析与体内功能基因组学相结合 在筛查中，我已经确定了多能因子KLF4在MET中富含，并且对肺转移至关重要。 该方案的目标是通过其作用确定KLF4对于OS转移是否是必要和充分的 维持和产生干细胞样增强子染色质。成功完成本研究将不会 不仅揭示了新的治疗靶点和预后生物标志物，而且还可能为患者的治疗提供信息 患有其他转移性癌症。

PROJECT SUMMARY While metastasis is the cause of >90% of cancer patient deaths, the majority of targeted therapies are developed based on the biology of the primary tumor. This discrepancy highlights the pressing clinical need to better understand what gives cancers the ability to colonize and thrive within a new microenvironment. For osteosarcoma (OS), there are no targeted anti-metastatic therapies, despite nearly all patients presenting with some degree of metastatic burden. Recent studies from our laboratory have demonstrated the process of OS lung metastasis is driven by alterations in the enhancer landscape. Metastasis-specific variant enhancer loci (met-VELs) are ubiquitous, and regulate genes critical for growth of this primary bone cancer within the lung. However, the heterogeneity of OS has limited the clinical translation of these findings. A unifying molecular mechanism upstream of the enhancer remodeling associated with metastasis will therefore provide novel nodes for therapeutic targeting. Combining comprehensive enhancer analysis with in vivo functional genomic screening, I have identified the pluripotency factor KLF4 as enriched at met-VELs and critical for lung metastasis. The goals of this proposal are to determine if KLF4 is necessary and sufficient for OS metastasis through its role in maintaining and generating stem cell-like enhancer chromatin. Successful completion of this study will not only reveal new therapeutic targets and prognostic biomarkers, but may also inform the treatment of patients suffering from other metastatic cancers.