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: 10519380
• 负责人: Patrick Viatour
• 金额: $ 30.9万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10519380
• 关键词: Mechanisms; tumor; initiation; upon; disruption

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 E2 f（E2 f1 -8）转录因子是细胞周期的关键调节因子，其活性受到物理调节 Rb家族蛋白（Rb，p107和p130）。Rb/E2 f相互作用的破坏是癌症的标志， 由Hanahan&温伯格定义。对这种破坏导致的抗生长信号的获得性抗性是 被认为是肿瘤发生所必需的。然而，不受限制的E2 f活性是如何启动肿瘤发生的？ 在体内是知之甚少，仍然是一个根本的差距，在我们的理解癌症生物学。在 特别是，分化状态是否影响细胞在Rb/E2 f破坏时转化的能力 相互作用是未知的。此外，不受限制的E2 f是否激活其他致癌特征， 异常增殖仍然不清楚。 肝细胞癌（HCC）是全球第二大死亡癌症。了解有限 频繁的遗传事件的功能后果阻碍了有效治疗的发展。 Rb/E2 f相互作用在绝大多数HCC中被破坏，这是靶向Rb/E2 f相互作用的几个事件的结果。 Rb/E2 f通路的上游组分。因此，HCC是一个相关的模型，以研究 不受限制的E2 f活性对癌症起始的后果。因此，Rb家族的泛肝失活 基因（三重敲除，TKO）足以启动HCC（TKO HCC），其重现了HCC的多种特征。 人类疾病。 对致癌物诱导的HCC模型的研究已经得出结论，肝细胞是唯一的肝细胞。 HCC的来源。Rb家族在肝细胞中的特异性失活触发了短暂的增殖爆发，但未能 启动HCC。这一结果挑战了该领域目前的以肝脏为中心的模型，并表明其他 谱系也可以作为HCC的起源细胞。因此，Rb家族在多个肝脏中的失活 谱系显示TKO HCC起源于导管周围祖细胞。特别是，我们的初步数据表明， 不受限制的E2 f活性将该群体中的异常增殖与细胞命运改变相结合， HCC。基于这些数据，我们提出：1）确定改变细胞命运的分子机制， 导管周祖细胞作为TKO HCC的起源细胞。2)确定个人和复合角色 E2 f因子在TKO HCC发生和发展中的作用3)确定TKO HCC的治疗弱点 可以作为新的治疗方法。 我们相信，我们的提案将解决有关E2 f在癌症中的作用的基本问题。 启动，如上所述。此外，我们希望我们的结果将建立不同的细胞谱系， 作为HCC的起源细胞，这将具有重要的临床意义，特别是关于 患者的分类和开发针对不同类型HCC的治疗。