Mechanisms of tumor initiation upon disruption of the Rb/E2f interaction

Rb/E2f 相互作用破坏后肿瘤发生的机制

• 批准号: 10210641
• 负责人: Patrick Viatour
• 金额: $ 10.64万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2021-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210641
• 关键词: Address; Affect; Automobile Driving; Back; Biological Assay; Cancer Biology; Carcinogens; Cell Cycle; Cell Differentiation process; Cell Lineage; Cells; Cessation of life; Classification; Clinical; Couples; Data; Development; Disease Progression; Duct (organ) structure; Event; Family; Frequencies; Gene Family; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hepatocyte; Human; Incidence; Individual; Knock-out; Knowledge; Lesion; Liver; Malignant Neoplasms; Methylation; Modeling; Molecular; Mus; Nature; Oncogenic; Oncoproteins; Organoids; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmacology; Population; Primary carcinoma of the liver cells; Protein Family; Resistance; Retinoblastoma Protein; Role; Sampling; Second Primary Cancers; Series; Signal Transduction; Source; Testing; Therapeutic; Validation; Viral; analytical tool; base; cancer initiation; epigenomics; functional genomics; human disease; in vivo; individualized medicine; mortality; neoplastic cell; novel; overexpression; progenitor; promoter; single-cell RNA sequencing; therapy development; transcription factor; tumor; tumor initiation; tumorigenesis

ABSTRACT E2f (E2f1-8) transcription factors are critical regulators of cell cycle and their activity is physically regulated by Rb family proteins (Rb, p107 and p130). Disruption of the Rb/E2f interaction is a hallmark of cancer, as defined by Hanahan&Weinberg. The acquired resistance to antigrowth signals resulting from this disruption is thought to be necessary for tumor initiation. However, how does unrestricted E2f activity initiates tumorigenesis in vivo is poorly understood and remains a fundamental gap in our understanding of cancer biology. In particular, whether the differentiation status affect the capacity of a cell to transform upon disruption of Rb/E2f interaction is unknown. In addition, whether unrestricted E2f activates other oncogenic features besides aberrant proliferation is still obscure. Hepatocellular carcinoma (HCC) is the second cancer in terms of death worldwide. Limited understanding of the functional consequences for frequent genetic events hampers the development of efficient therapeutics. The Rb/E2f interaction is disrupted in the vast majority of HCC, as a consequence of several events that target upstream components of the Rb/E2f pathway. Therefore, HCC is a relevant model to investigate the consequences of unrestricted E2f activity for cancer initiation. Accordingly, pan-liver inactivation of Rb family genes (Triple Knock Out, TKO) is sufficient to initiate HCC (TKO HCC) that recapitulate multiple features of the human disease. Studies of carcinogen-induced models of HCC have led to the conclusion that hepatocytes are the sole source of HCC. Specific inactivation of Rb family in hepatocytes triggers a short proliferative burst but fails to initiate HCC. This result challenges the current hepato-centric model in the field and suggests that other lineages can also serve as a cell of origin for HCC. Accordingly, inactivation of Rb family in multiple liver lineages reveals that TKO HCC arises from a periductal progenitor. In particular, our preliminary data indicates that unrestricted E2f activity couples aberrant proliferation with cell fate alteration in this population to initiate HCC. Based on these data, we propose to:1) determine the molecular mechanisms that alter the cell fate of a periductal progenitor to serve as a cell of origin for TKO HCC. 2) determine the individual and compound role of E2f factors in TKO HCC initiation and development. 3) determine therapeutic vulnerabilities in TKO HCC that could serve as novel treatment for patients. We believe that our proposal will address fundamental questions regarding the role of E2f in cancer initiation, as identified above. In addition, we expect that our results will establish that different cell lineages can serve as a cell of origin for HCC, which will have important clinical implications, in particular regarding the classification of patients and the development of therapies tailored for different classes of HCC.

摘要 E2F(E2F1-8)转录因子是细胞周期的关键调节因子，其活性受物理调控 Rb家族蛋白(Rb、p107和p130)。Rb/E2F相互作用的中断是癌症的一个标志，因为 由Hanahan&Weinberg定义。这种干扰导致的对抗生长信号的获得性抵抗力是 被认为是启动肿瘤所必需的。然而，不受限制的E2F活动是如何启动肿瘤发生的 在体内的了解很少，仍然是我们对癌症生物学理解的一个根本差距。在……里面 具体地说，分化状态是否影响细胞在Rb/E2F中断时的转化能力 相互作用是未知的。此外，不受限制的E2F是否激活了除 异常增殖仍不清楚。 肝细胞癌是世界范围内死亡人数第二多的癌症。有限的理解 频繁遗传事件的功能后果阻碍了有效疗法的发展。 在绝大多数肝癌中，RB/E2F相互作用被中断，这是几个靶向事件的结果 Rb/E2F途径的上游组件。因此，肝细胞癌是一个相关的模型来研究 不受限制的E2F活动对癌症启动的影响。因此，泛肝脏失活的Rb家族 基因(三重敲除，TKO)足以启动肝细胞癌(TKO肝细胞癌)，概括了 人类疾病。 对致癌物诱导的肝细胞癌模型的研究得出结论，肝细胞是唯一的 肝癌的来源。肝细胞中Rb家族的特异性失活可触发短暂的增殖爆发，但不能 启动肝细胞癌。这一结果对目前该领域以肝脏为中心的模式提出了挑战，并表明其他 谱系也可以作为肝细胞癌的起源细胞。相应地，Rb家族在多个肝脏中失活 谱系显示，TKO肝细胞癌起源于导管周围祖细胞。特别是，我们的初步数据表明 在这个群体中，不受限制的E2F活动将异常增殖与细胞命运改变结合在一起，以启动 肝细胞癌。基于这些数据，我们建议：1)确定改变细胞命运的分子机制 导管周围祖细胞可作为TKO肝细胞癌的起源细胞。2)确定个人角色和复合角色 E2F因子在TKO肝细胞癌发生发展中的作用3)确定TKO肝细胞癌的治疗脆弱性 这可能为患者提供新的治疗方法。 我们相信，我们的建议将解决有关E2F在癌症中的作用的根本问题 启蒙，如上所述。此外，我们预计我们的结果将确定不同的细胞谱系可以 作为肝细胞癌的起源细胞，这将具有重要的临床意义，特别是关于 针对不同类型的肝细胞癌患者的分类和治疗方法的发展。