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.

项目概要 大多数胰腺导管腺癌 (PDA) 患者出现晚期转移性疾病 它通常对治疗有抵抗力，导致存活率极低。 调节 PDA 的早期启动和进展对于开发新的、更多的药物至关重要 准确的胰腺癌模型用于鉴定生物标志物和新的治疗靶点蛋白质。 磷酸酶是细胞信号传导途径（包括 MAPK 和 PI3K 途径）的主要调节因子。 我们实验室和其他实验室的研究表明，PDA 肿瘤中 PP2A 的表达增加 抑制剂和相应的 PP2A 功能下降，表明 PP2A 的抑制是一种常见的 PDA 进展中的活性 PP2A 全酶由三种蛋白质组成，其中包括催化蛋白质。 亚基、支架亚基和提供靶标特异性的调节 (B) 亚基。 被认为具有肿瘤抑制因子的功能，特定 B 亚基对疾病的个体贡献 我们对 PP2A B 亚基 B56 的进展仍知之甚少。 KRAS 驱动途径的调节器，包括癌蛋白 c-MYC 的稳定。 90-95% 的 PDA 患者发生突变，B56 对该通路的调节代表了 在我们的初步研究中，小鼠 B56α 的缺失加速了胰腺前体的形成。 病变并增加参与细胞命运和转移的转录因子的表达。 研究发现 B56 在介导胰腺细胞可塑性方面发挥着关键作用，并且 B56 的抑制 会增加胰腺细胞对致癌突变的敏感性，驱动 PDA 启动和 该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复合物形成和功能的影响，2）检查B56是否丢失 加速体外和体内癌前病变的进展，3) 确定治疗是否有效 PP2A-B56 的激活可以抑制 PDA 过程中发生的转录和表观遗传变化 这些研究将利用单细胞表观遗传分析、小鼠等技术。 PDA 建模，并使用循环免疫荧光分析人 PDA 肿瘤中的 PP2A 组成 为了提供与磷酸酶功能相关的 PDA 发育的深入分子理解。 重要的是，早期肿瘤过程中涉及细胞可塑性的因子的转录失调 发展已被证明对晚期肿瘤异质性、亚型和 因此，这些治疗研究的结果将为未来提供坚实的基础。 对早期和晚期疾病的询问，扩大了我的独立科学计划和 支持我了解 PDA 分子基础的长期目标。