Unraveling KLF4 dependency in metastatic osteosarcoma

揭示转移性骨肉瘤中 KLF4 的依赖性

• 批准号: 10377904
• 负责人: William Dean Pontius
• 金额: $ 4.68万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377904
• 关键词: Affect; Binding; Biological Assay; Biology; CRISPR/Cas technology; Cancer Patient; Cell Line; Cells; Cessation of life; ChIP-seq; Chemicals; Child; Childhood; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Competence; DNA; Data; Dependence; Diagnosis; Disease; Disseminated Malignant Neoplasm; Drug resistance; Enhancers; Epigenetic Process; Essential Genes; Family; Fibrinogen; GKLF protein; Genes; Genetic; Genetic Enhancer Element; Genomic Instability; Goals; Growth; Guide RNA; Heterogeneity; Histones; Human; In Vitro; Knock-out; Laboratories; Learning; Libraries; Link; Lung; Malignant Bone Neoplasm; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Metastatic to; Mind; Modeling; Molecular; Mutagenesis; Neoplasm Metastasis; Nonmetastatic; Oncogenic; Patient Care; Patients; Phenotype; Play; Pluripotent Stem Cells; Predictive Factor; Primary Neoplasm; Process; Prognostic Marker; Property; RB1 gene; Recurrence; Role; Signal Transduction; Somatic Cell; Survival Rate; TP53 gene; Testing; Upstream Enhancer; Variant; base; bone; cancer stem cell; clinical translation; cohort; daughter cell; driver mutation; epigenome; functional genomics; genome-wide; improved; in vivo; loss of function; lung colonization; lung metastatic; mortality; mouse model; new therapeutic target; novel; osteosarcoma; overexpression; pluripotency factor; primary bone cancer; screening; stem; stem cells; stem-like cell; stemness; success; targeted biomarker; targeted treatment; therapeutic target; therapy development; transcription factor; tumorigenic; young adult

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.

项目摘要 虽然转移是>90%的癌症患者死亡的原因，但大多数靶向治疗都是由肿瘤转移引起的。 基于原发肿瘤的生物学特性这种差异突出了临床上迫切需要更好地 了解是什么赋予了癌症在新的微环境中定植和生长的能力。为 骨肉瘤（OS），没有靶向抗转移治疗，尽管几乎所有患者都表现为 一定程度的转移负荷。我们实验室最近的研究表明， 肺转移是由增强子分布的改变驱动的。转移特异性变异增强子基因座 （met-VEL）是普遍存在的，并且调节对于肺内这种原发性骨癌的生长至关重要的基因。 然而，OS的异质性限制了这些结果的临床转化。一个统一的分子 因此，与转移相关的增强子重塑上游机制将提供新的淋巴结 用于治疗靶向。结合全面的增强子分析和体内功能基因组学 通过筛选，我已经鉴定了多能性因子KLF 4在met-VEL处富集并且对于肺转移是关键的。 本提案的目标是确定KLF 4是否是OS转移所必需的，是否足以通过其作用 维持和产生干细胞样增强染色质。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，而且还可以为患者的治疗提供信息。 患有其他转移性癌症。