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The role of PP2A B56a in pancreatic tumorigenesis

PP2A B56a 在胰腺肿瘤发生中的作用

基本信息

批准号：
10241986
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
项目类别：
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/10241986
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 KRAS oncogenesis KRAS2 gene KRASG12D 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 ductal adenocarcinoma model 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

项目摘要

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.

项目总结