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: 10738337
• 负责人: NABEEL El-BARDEESY
• 金额: $ 23.38万
• 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/10738337
• 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）是人类所有恶性肿瘤中最致命的一种。一个关键 临床挑战是这些肿瘤早期侵袭和转移的倾向。因此，大多数患者 不适合切除的患者，以及经常复发的患者。这一挑战因以下因素而更加复杂： 缺乏早期检测侵袭性疾病的方法， PDA进展的机制。我们发现胎儿RNA结合蛋白Lin 28 b是一种主要的 PDA转移中的驱动因素提供了一个框架，以解决这种多重PI中的这些关键问题。 提议在以前的研究中，我们发现癌胚RNA结合蛋白Lin 28 b在肿瘤细胞中高度表达。 在鼠模型和人类患者样品中，PDA中的表达上调。此外，新的初步数据 表明Lin 28 b在从患有癌症的患者获得的循环肿瘤细胞（CTC）中特异性上调， 早期可切除PDA。基于这些发现，我们假设Lin 28 b驱动PDA进展， 通过重编程细胞分化向更原始的祖细胞样状态转移， CTC中Lin 28 b的检测可以用作疾病侵袭性的分子信标。 为了验证这一假设，我们将：1-将Lin 28 b表征为人类自我更新和肿瘤进展驱动因子 和鼠PDA模型。我们将利用来自人CTC的离体生长的类器官和特异性的细胞因子。 PDA的基因工程小鼠模型，以遗传操作Lin 28 b并确定肿瘤 增殖细胞功能和驱动PDA进展的能力。2-确定机制， Lin 28 b可以驱动攻击性，探索其下游靶点（与microRNA let-7相关）， 由这种癌胚蛋白驱动的生物学和代谢特征。3-评价Lin 28 b作为预测性生物标志物 PDA早期疾病复发，利用从接受手术的人类患者中分离的CTC 切除术

项目成果

Quasimesenchymal phenotype predicts systemic metastasis in pancreatic ductal adenocarcinoma.

准间充质表型预测胰腺导管腺癌的全身转移。

• DOI: 10.1038/s41379-018-0196-2
• 发表时间: 2019
• 期刊: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
• 作者: Mahadevan,KrishnanK;Arora,KshitijS;Amzallag,Arnaud;Williams,Erik;Kulkarni,AnupriyaS;Fernandez-DelCastillo,Carlos;Lillemoe,KeithD;Bardeesy,Nabeel;Hong,TheodoreS;Ferrone,CristinaR;Ting,DavidT;Deshpande,Vikram
• 通讯作者: Deshpande,Vikram