Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression

Lin28b 在胰腺癌进展中作用的机制理解

• 批准号: 10559707
• 负责人: NABEEL El-BARDEESY
• 金额: $ 56.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-19 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559707
• 关键词: Address; Adult; Automobile Driving; Binding; Biological; Biological Assay; Biological Markers; Biological Models; Biology; Blood; Cell Differentiation process; Cell Reprogramming; Cell Separation; Cell physiology; Cells; Cellular Metabolic Process; Characteristics; Chromatin; Clinical; Credentialing; DNA Repair; Data; Dependence; Detection; Developmental Gene; Diagnostic; Differentiation and Growth; Disease; Early Diagnosis; Epigenetic Process; Excision; Foundations; Genes; Genetic Transcription; Genetically Engineered Mouse; Glycolysis; Growth; HMGA2 gene; Human; In Vitro; Invaded; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Messenger RNA; Metabolic; Metabolism; Methods; MicroRNAs; Modeling; Molecular; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Nonmetastatic; Operative Surgical Procedures; Organoids; Outcome; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Phenotype; Primary Neoplasm; Progression-Free Survivals; Proteomics; RNA; RNA-Binding Proteins; Recurrent disease; Regulator Genes; Relapse; Resectable; Role; Sampling; Site; Somatic Cell; Specimen; Testing; Tissues; Tumor Suppressor Proteins; Tumor Tissue; Undifferentiated; Work; chemotherapy; clinical biomarkers; data integration; disease natural history; early detection biomarkers; experimental study; fetal; gene network; genetic manipulation; histone demethylase; implantation; in vivo; loss of function; migration; mouse model; neoplastic cell; novel; oncofetal antigen; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pluripotency; predictive marker; progenitor; programs; promoter; recruit; self-renewal; single cell analysis; stem cell genes; transcriptome sequencing; tumor; tumor progression

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal of all human malignancies. A key clinical challenge is the propensity of these tumors for early invasion and metastasis. Thus, most patients are not eligible for resection, and those who are often show recurrent disease. This challenge is compounded by the absence of methods for early detection of invasive disease and incomplete understanding of the mechanisms for PDA progression. Our discovery of the fetal RNA-binding protein Lin28b as a major driver in PDA metastasis provides a framework to address these critical issues in this multiple-PI proposal. In previous studies, we have found that the oncofetal RNA-binding protein Lin28b is highly upregulated in PDA, both in murine models and human patient samples. Furthermore, new preliminary data indicate that Lin28b is specifically upregulated in Circulating Tumor Cells (CTCs) obtained from patients with early resectable PDA. Based on these findings, we hypothesize that Lin28b drives PDA progression and metastasis by reprogramming cell differentiation toward a more primitive progenitor-like state, and that detection of Lin28b in CTCs can serve as a molecular beacon for disease aggressiveness.In order to test this hypothesis, we will: 1- Characterize Lin28b as a driver of self renewal and tumor progression in human and murine PDA models. We will take advantage of ex-vivo grown organoids from human CTCs and specific genetically engineered mouse models of PDA to genetically manipulate Lin28b and determine tumor propagating cell function and ability to drive PDA progression. 2- Determine the mechanisms through which Lin28b could drive agressiveness, exploring its downstream targets (linked to the microRNA let-7), and the biological and metabolic features driven by this oncofetal protein. 3- Evaluate Lin28b as a predictive biomarker of PDA early disease recurrence, taking advantage of CTCs isolated from human patients undergoing surgical resection.

胰腺导管腺癌(PDA)是人类最致命的恶性肿瘤之一。一把钥匙 临床挑战是这些肿瘤的早期侵袭和转移的倾向。因此，大多数患者都是 没有资格切除的，以及那些经常表现出复发的疾病。这一挑战因以下原因而变得复杂 缺乏早期发现侵袭性疾病的方法，对侵袭性疾病的认识不全面 PDA进展的机制。我们发现胎儿RNA结合蛋白Lin28b是一种主要的 PDA转移的驱动因素提供了一个框架来解决这些关键问题 求婚。在以前的研究中，我们已经发现肿瘤胎儿rna结合蛋白lin28b高度 无论是在小鼠模型还是在人类患者样本中，PDA都表达上调。此外，新的初步数据 提示Lin28b在慢性粒细胞白血病患者的循环肿瘤细胞(CTCs)中特异性上调 早期可切除动脉导管未闭。基于这些发现，我们假设Lin28b驱动PDA进展和 通过将细胞分化重新编程为更原始的祖细胞样状态而转移，并且 检测CTCs中Lin28b的表达可作为判断疾病侵袭性的分子灯塔。 验证这一假设，我们将：1-将Lin28b描述为人类自我更新和肿瘤进展的驱动因素 和小鼠掌上电脑模型。我们将利用体外培养的来自人类CTCs的有机类化合物和特定的 基因工程小鼠PDA模型对Lin28b进行基因操作并确定肿瘤 传播细胞功能和推动PDA进展的能力。2-确定通过哪些机制 Lin28b可以通过探索其下游靶标(与microRNA let-7相连)来推动侵袭性，而 由这种致癌胎儿蛋白驱动的生物学和代谢特征。3-评估Lin28b作为预测生物标志物 利用从手术患者身上分离的CTCs预防PDA早期疾病复发 切除手术。