Mechanisms of p53 Engagement and Action at the Benign-to-Malignant Transition in Sporadic Tumorigenesis

p53在散发性肿瘤发生良性向恶性转变中的参与和作用机制

基本信息

批准号：
10720034
负责人：
SCOTT W. LOWE
金额：
$ 72.69万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-03 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10720034
关键词：
Acceleration Address Apoptosis Back Benign Biological Cell Proliferation Cell Survival Cell physiology Cells Computer Analysis Consensus DNA Damage DNA Methylation Data Development Disease Disease Progression Event Gene Expression Genetic Genetic Transcription Genome Stability Genomic Instability High Prevalence Human Injury Intercept KRAS oncogenesis KRAS2 gene Knowledge Lesion Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Maps Metabolism Modeling Mus Mutate Mutation Mutation Detection Neoplasms Neoplastic Cell Transformation Null Lymphocytes Oncogene Activation Oncogenes Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Ductal Carcinoma Polyploidy Precancerous Conditions Premalignant Cell Process Prognosis Research Role Signal Transduction TP53 gene Testing Tumor Promotion Tumor Suppressor Proteins Work cancer initiation cancer prevention cancer therapy cancer type cell transformation computerized tools in vivo insight mouse model mutant neoplastic cell novel premalignant prevent programs restoration senescence single cell analysis tool transcription factor tumor tumor heterogeneity tumorigenesis

项目摘要

PROJECT SUMMARY The transcription factor p53 is one of the most critical barriers to tumorigenesis. p53 is mutated in over half of all human tumors, and p53-mutant tumors typically carry a worse prognosis. As a tumor suppressor, p53 appears to act at the transition from benign to malignant disease, preventing transformation of cells that have already acquired some pro-tumor features, such as oncogene activation or DNA damage. Decades of research have sought to identify what makes p53 a potent tumor suppressor, as such knowledge could inform effective strategies for cancer prevention and treatment. This research has shown that p53 can be activated by a variety of signals, and in turn activated p53 can regulate a wide variety of cellular processes, including cell survival, senescence, genomic stability, and plasticity. However, the inducers and actions of p53 vary with context, and there is still no consensus on what signals engage p53 during early neoplasia and what biological programs are most important for its tumor-suppressive functions. Furthermore, we still do not know the key events following p53 loss that enable transition to malignancy. Attempts to gain this knowledge have been hampered by a lack of tools to directly study p53 in the specific cells undergoing transformation within endogenous contexts. To address these gaps in knowledge, we will study the events surrounding p53 activation and loss during the initiation of pancreatic ductal carcinoma (PDAC), an aggressive cancer in which p53 loss—which occurs in 70% of PDACs—enables progression from benign precursor lesions to full-blown cancer. We recently developed new mouse models of PDAC that allow us to “see” p53 in action as cells progress through the benign-to-malignant transition. Among the premalignant pancreas cells, we discovered a subpopulation that shares many transcriptional features with established tumor cells, and thus these cells appear to be transitioning from premalignant to malignant. These transitioning cells are also the cells with the strongest p53 activation, and so they provide a unique opportunity to study p53 engagement and tumor-suppressive function at the benign-to-malignant transition. Using single-cell transcriptional and spatial analyses, new computational approaches to infer cell state transitions, and our well-established platform for rapid genetic perturbations in vivo, we will define the cell-intrinsic and cell-extrinsic events that lead to this p53-active transitioning cell state. Furthermore, we will investigate the mechanisms by which activated p53 suppresses neoplastic transformation in the transitioning cells, as well as the events that influence cancer initiation immediately following p53 loss. This project will provide novel insight into the mechanisms that drive PDAC initiation and provide a direct and detailed characterization of p53 in action in endogenous contexts. Given the high prevalence of TP53 mutations in human cancers, we expect the insights into tumorigenesis to be applicable to many cancer types.

项目概要转录因子 p53 是肿瘤发生最关键的障碍之一，超过一半的人会发生 p53 突变。所有人类肿瘤和 p53 突变肿瘤通常预后较差。似乎在良性疾病向恶性疾病的转变过程中发挥作用，防止已患有疾病的细胞发生转化。数十年的研究已经获得了一些促肿瘤特征，例如癌基因激活或DNA损伤。我们试图找出 p53 成为有效肿瘤抑制因子的原因，因为这些知识可以为有效的肿瘤抑制提供信息这项研究表明 p53 可以被多种激活。信号，进而激活 p53 可以调节多种细胞过程，包括细胞存活、然而，p53 的诱导物和作用随环境而变化。对于早期肿瘤形成期间 p53 的参与信号以及什么生物程序仍没有达成共识最重要的是它的肿瘤抑制功能。此外，我们仍然不知道其中的关键事件。 p53 缺失导致转变为恶性肿瘤后，获取这方面知识的尝试受到了阻碍。由于缺乏直接研究内源性转化的特定细胞中 p53 的工具为了解决这些知识空白，我们将研究有关 p53 激活和丢失的事件。胰腺导管癌 (PDAC) 是一种侵袭性癌症，其中 p53 缺失，在其发生过程中 70% 的 PDAC 中发生这种现象，使得良性前驱病变进展为全面的癌症。最近开发了新的 PDAC 小鼠模型，使我们能够“看到”p53 在细胞进展过程中的作用。在癌前胰腺细胞中，我们发现了一个亚群。许多细胞与已建立的肿瘤细胞具有转录特征，因此这些细胞似乎是从癌前细胞向恶性细胞转变的细胞也是 p53 最强的细胞。激活，因此它们提供了研究 p53 参与和肿瘤抑制功能的独特机会使用单细胞转录和空间分析，新的计算。推断细胞状态转变的方法，以及我们完善的快速遗传扰动平台在体内，我们将定义导致这种 p53 活性转变细胞状态的细胞内在和细胞外在事件。此外，我们将研究激活的 p53 抑制肿瘤转化的机制以及 p53 缺失后立即影响癌症发生的事件。该项目将为驱动 PDAC 启动的机制提供新颖的见解，并提供直接和鉴于 TP53 的高患病率，p53 在内源性环境中发挥作用的详细特征。人类癌症的突变，我们期望对肿瘤发生的见解适用于许多癌症类型。