Unraveling KLF4 dependency in metastatic osteosarcoma

揭示转移性骨肉瘤中 KLF4 的依赖性

• 批准号: 10579953
• 负责人: William Dean Pontius
• 金额: $ 4.77万
• 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/10579953
• 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; Endowment; Enhancers; Epigenetic Process; Essential Genes; Family; 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; Modeling; Molecular; Mutagenesis; Neoplasm Metastasis; Nonmetastatic; Oncogenic; Patient Care; Patients; Phenotype; Pluripotent Stem Cells; Predictive Factor; Primary Neoplasm; Process; Prognostic Marker; Proliferating; Property; RB1 gene; Recurrence; Role; Signal Transduction; Somatic Cell; Survival Rate; TP53 gene; Testing; Upstream Enhancer; Variant; 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; statistics; stem; stem cells; stem-like cell; stemness; success; targeted biomarker; targeted treatment; therapeutic biomarker; 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 虽然转移是癌症患者死亡> 90％的原因，但大多数靶向疗法是开发的 基于原发性肿瘤的生物学。这种差异突出了紧迫的临床需求 了解是什么使癌症能够在新的微环境中殖民和繁荣发展。为了 骨肉瘤（OS），尽管几乎所有患者都出现在 某种程度的转移负担。我们实验室的最新研究证明了OS的过程 肺转移是由增强剂景观改变的驱动。转移特异性变体增强子基因座 （Met-vels）无处不在，调节基因对肺内原发性骨癌的生长至关重要。 但是，OS的异质性限制了这些发现的临床翻译。统一的分子 因此，增强子重塑与转移相关的机制将提供新的节点 用于治疗靶向。将综合增强子分析与体内功能基因组相结合 筛选，我已经确定多能因子klf4富含Met-vels，对肺转移至关重要。 该提案的目标是确定KLF4是否有必要且足以使OS转移通过其角色 在维持和生成干细胞样增强子染色质时。成功完成这项研究将不会 仅揭示新的治疗靶标和预后生物标志物，但也可能告知患者的治疗 患有其他转移性癌症。