The role of PP2A B56a in pancreatic tumorigenesis

PP2A B56a 在胰腺肿瘤发生中的作用

• 批准号: 9976962
• 负责人: Brittany Allen-Petersen
• 金额: $ 17.48万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976962
• 关键词: 3-Dimensional; Acinar Cell; Address; Attenuated; Automobile Driving; Behavior; Biological Assay; Cancer Biology; Cancer Etiology; Catalytic Domain; Cells; Cessation of life; Chromatin; Colon Carcinoma; Complex; Data; Development; Disease; Disease Progression; Duct (organ) structure; Epigenetic Process; Event; Exhibits; Future; Genetic; Genetic Transcription; Goals; Holoenzymes; Human; Immunofluorescence Immunologic; In Vitro; Individual; KRAS2 gene; Knowledge; Lesion; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metaplasia; Molecular; Mus; Mutation; Neoplasm Metastasis; Normal Cell; Oncogenic; Oncoproteins; Organoids; PPP2R5A gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Periodicity; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Predisposition; Protein Analysis; Protein Dephosphorylation; Protein Inhibition; Protein Serine/Threonine Phosphatase; Protein phosphatase; Proteins; Refractory; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Specificity; Survival Rate; Techniques; Testing; Therapeutic; Time; Tumor Suppressor Proteins; Tumor Tissue; Tumor stage; Up-Regulation; Work; aggressive therapy; biomarker identification; c-myc Genes; cancer cell; cancer initiation; epigenomics; genome-wide; in vivo; inhibitor/antagonist; mRNA Expression; mouse model; new therapeutic target; novel; pancreatic cancer model; pancreatic cancer patients; pancreatic tumorigenesis; premalignant; programs; protein activation; protein expression; scaffold; small molecule; therapy resistant; transcription factor; treatment response; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression; tumorigenic

Project Summary The majority of pancreatic ductal adenocarcinoma (PDA) patients present with late-stage, metastatic disease that is often resistant to therapeutics, resulting in extremely low survival rates. Understanding the mechanisms that regulate the early initiation and progression of PDA is critically important to the development of new, more accurate pancreatic cancer models for the identification of biomarkers and novel therapeutic targets. Protein phosphatases are master regulators of cell signaling pathways, including the MAPK and PI3K pathways. Studies from our lab and others have demonstrated that PDA tumors have increased expression of PP2A inhibitors and a corresponding decrease in PP2A function, suggesting that the inhibition of PP2A is a common event in PDA progression. The active PP2A holoenzyme is composed of three proteins including a catalytic subunit, a scaffolding subunit, and a regulatory (B) subunit that provides target specificity. While PP2A is thought to function as a tumor suppressor, the individual contribution of specific B subunits to disease progression is still poorly understood. We have identified the PP2A B subunit, B56, as being an important regulator of KRAS driven pathways, including the stabilization of the oncoprotein c-MYC. Given that KRAS mutations occur in 90-95% of PDA patients, regulation of this pathway by B56 represents an important gap in knowledge. In our preliminary studies, loss of B56 in mice accelerated the formation of pancreatic precursor lesions and increased the expression of transcription factors involved in cell fate and metastasis. Therefore, I hypothesize that B56 plays a critical role in mediating pancreatic cell plasticity, and that suppression of B56 will increase the susceptibility of pancreatic cells to oncogenic mutation, driving PDA initiation and transformation. This hypothesis will be addressed through the following three Specific Aims: 1) Determine the impact of oncogenic KRAS on PP2A-B56 complex formation and function, 2) Examine whether loss of B56 accelerates the progression of premalignant lesions in vitro and in vivo, and 3) Determine if therapeutic activation of PP2A-B56 can suppress the transcriptional and epigenetic changes that occur during PDA initiation. These studies will take advantage of techniques such as single cell epigenetic analysis, mouse modeling of PDA, and analysis of PP2A composition in human PDA tumors using cyclic immunofluorescence in order to provide a deep molecular understanding of PDA development in relation to phosphatase function. Importantly, the transcriptional deregulation of factors involved in cellular plasticity during early tumor development has been shown to have a significant impact on late stage tumor heterogeneity, subtype, and therapeutic response. Therefore, results from these studies will provide a strong basis for the future interrogation of both early and late stage disease, expanding my independent scientific program and supporting my long-term goal of understanding the molecular basis of PDA.

项目摘要 大多数胰腺导管腺癌(PDA)患者存在晚期转移性疾病 这往往对治疗产生抵抗力，导致存活率极低。了解相关机制 调节PDA的早期启动和进展对于开发新的、更多的 准确的胰腺癌模型用于识别生物标记物和新的治疗靶点。蛋白 磷酸酶是细胞信号通路的主要调节者，包括MAPK和PI3K通路。 我们实验室和其他实验室的研究表明，PDA肿瘤增加了PP2A的表达 抑制剂和相应的PP2A功能下降，提示PP2A的抑制是一种常见的 PDA进展中的事件。具有活性的PP2A全酶由三种蛋白质组成，包括一种催化 亚基、支架亚基和提供靶向特异性的调节(B)亚基。而PP2A是 被认为具有肿瘤抑制作用的特定B亚单位对疾病的个体贡献 进展情况仍鲜为人知。我们已经确定PP2A B亚单位B56是一个重要的 调节KRAS驱动的通路，包括稳定癌蛋白c-myc。鉴于KRAS 突变发生在90-95%的PDA患者中，B56对这一途径的调节是一个重要的缺口 知识。在我们的初步研究中，小鼠体内B56的缺失加速了胰腺前体的形成 并增加参与细胞命运和转移的转录因子的表达。因此，我 假设B56在介导胰腺细胞可塑性中起关键作用，并抑制B56 将增加胰腺细胞对癌基因突变的易感性，推动PDA的启动和 转型。这一假设将通过以下三个具体目标来解决：1)确定 致癌KRAs对PP2A-B56复合体形成和功能的影响2)检测B56是否丢失 在体外和体内加速癌前病变的进展，以及3)确定是否具有治疗作用 PP2A-B56的激活可以抑制动脉导管未闭期间的转录和表观遗传变化 入会仪式。这些研究将利用单细胞表观遗传学分析、小鼠 人PDA模型的建立及肿瘤组织中PP2A成分的循环免疫荧光分析 以便从分子水平上深入了解PDA与磷酸酶功能的关系。 重要的是，参与细胞可塑性的转录因子在早期肿瘤中的转录失控 发展已被证明对晚期肿瘤的异质性、亚型和 治疗反应。因此，这些研究的结果将为未来的研究提供强有力的基础 对早期和晚期疾病的审问，扩大了我的独立科学计划和 支持我理解掌上电脑分子基础的长期目标。