Investigating cells of origin and oncogenic modifiers of 3q26-driven LUSC

研究 3q26 驱动的 LUSC 的起源细胞和致癌修饰因子

基本信息

批准号：
10593501
负责人：
Alan P. Fields
金额：
$ 7.37万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593501
关键词：
3q26 Accounting Alleles Alveolar Auranofin Biochemical Biogenesis Bioinformatics Biological Biological Markers Cancer Etiology Cells Cessation of life Chromosomes Clinical Combined Modality Therapy Data Diagnosis Drug Combinations Enterobacteria phage P1 Cre recombinase Event Exhibits Genes Genetic Genetic Recombination Genetic Transcription Genetic study Genetically Engineered Mouse Genomics Growth Histologic Human In Vitro Intervention Keratin Knock-in Knock-out Knowledge Lesion Lung Lung Adenocarcinoma Lung Neoplasms MEKs Malignant Epithelial Cell Malignant neoplasm of lung Modeling Molecular Profiling Morphology Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Outcome Pathway interactions Patients Pharmacology Phenotype Play Prognosis Property Proteins Recurrence Relapse Resources Ribosomal DNA Ribosomes Role Signal Transduction Signaling Protein Squamous Cell Lung Carcinoma Squamous cell carcinoma Structure of parenchyma of lung TP53 gene Testing Therapeutic Therapeutic Intervention Transgenes Tumor-Derived United States World Health Organization alveolar type II cell base biological heterogeneity cancer diagnosis cell growth cell transformation clinically relevant conditional knockout design druggable target early detection biomarkers genomic signature improved in vivo inhibitor insight mouse model neoplastic cell new therapeutic target notch protein novel novel therapeutic intervention overexpression parent grant pharmacodynamic biomarker pre-clinical predictive marker premalignant programs promoter recombinant adenovirus response self-renewal stem cells targeted treatment treatment response tumor tumor growth tumor heterogeneity tumor initiation tumor progression tumorigenesis

项目摘要

Project Abstract Lung squamous cell carcinoma (LUSC) is a major subtype of lung cancer accounting for ~30% of all lung cancer diagnoses. LUSC patients suffer from poor therapeutic response, high relapse rate, and poor prognosis. A major reason for this bleak outcome is a lack of well characterized oncogenic drivers of LUSC that can be targeted therapeutically. We have identified concomitant 3q26 copy number gain (CNG) and TP53 loss as defining genetic alterations present in ~90% of LUSC tumors.2 Furthermore, we have identified 3 3q26 oncogenes, PRKCI, ECT2 and SOX2, that genetically and biochemically collaborate to drive LUSC tumor formation.2-4 We have developed the first genetically engineered mouse model (GEMM) to study these genetic alterations in LUSC tumorigenesis in vivo.1 Our GEMM allows inducible overexpression of Prkci, Ect2, and Sox2 and knockout of Trp53 (PES/Trp53-/-) in lung tissue. Specific Aims of the parent grant are to: 1) evaluate the effect of pharmacologic inhibitors of PKCι (the protein product of PRKCI) and PKCι effector pathways on PES/Trp53-/--driven LUSC; and 2) characterize tumor initiation and progression in our PES/Trp53-/- LUSC GEMM from lung basal stem cells (LBSCs), a major cell of origin for LUSC. Interestingly, two other regional lung stem cells (Club and alveolar type II (AT2) cells) can also serve as cells of origin for LUSC.5-7 Moreover, we have identified additional genes within the recurrent 3q26 amplicon that may play promotive roles in PES/Trp53-/--driven LUSC. Based on these new observations, we hypothesize that: 1) PES/Trp53-/- mice can develop LUSC tumors from multiple cells of origin, giving rise to LUSC tumors with distinct biological, genomic and biochemical properties; and 2) additional genes within the 3q26 amplicon contribute to PES/Trp53-/--driven LUSC. These hypotheses will be tested through two interrelated specific aims designed to: 1) To assess the ability of PES/Trp53-/- mice to generate LUSC tumors from Club and AT2 cells in vivo; and 2) determine genomic and molecular signatures of PES/Trp53-/--driven LUSC tumors from distinct cells of origin. This supplement project is a significant extension of Aim 2 of the parent grant which proposes to characterize a novel GEMM of PES/Trp53-/--driven LUSC from LBSCs. The proposed studies will expand the parent grant by: 1) assessing the role of alternative cells of origin (Club and AT2 lung stem cells) in LUSC tumor formation; 2) identifying genomic and molecular signatures of LUSC tumors arising from LBSC, Club, and AT2 lung stem cells; and 3) characterizing the role of recently identified 3q26 genes as possible modifiers of LUSC tumorigenesis. Completion of these studies will provide novel insights into biological heterogeneity observed in LUSC tumors harboring 3q26 CNG and identify oncogenic signaling pathways and genes that may be useful as biomarkers of LUSC tumorigenesis and serve as targets for therapeutic intervention.

项目摘要肺鳞状细胞癌 (LUSC) 是肺癌的主要亚型，约占所有肺癌的 30% LUSC 患者的治疗反应差、复发率高、诊断效果差。这种黯淡结果的一个主要原因是缺乏明确的 LUSC 致癌驱动因素。我们已经确定了伴随的 3q26 拷贝数增益 (CNG) 和 TP53 缺失定义了约 90% 的 LUSC 肿瘤中存在的基因改变。2 此外，我们还发现了 3 3q26 癌基因 PRKCI、ECT2 和 SOX2，通过遗传和生化作用共同驱动 LUSC 肿瘤 2-4 我们开发了第一个基因工程小鼠模型（GEMM）来研究这些基因体内 LUSC 肿瘤发生的改变。1 我们的 GEMM 允许诱导性过度表达 Prkci、Ect2 和肺组织中的 Sox2 和 Trp53 (PES/Trp53-/-) 敲除的具体目标是： 1) 评估。 PKCι（PRKCI 的蛋白质产物）和 PKCι 效应途径的药物抑制剂对 PES/Trp53-/--driven LUSC；2) 表征 PES/Trp53-/- LUSC 中的肿瘤发生和进展 GEMM 来自肺基底干细胞 (LBSC)，这是 LUSC 的主要来源细胞，还有另外两个区域。肺干细胞（Club 和肺泡 II 型 (AT2) 细胞）也可以作为 LUSC.5-7 的起源细胞。我们已经在循环 3q26 扩增子中鉴定出其他基因，这些基因可能在以下方面发挥促进作用： PES/Trp53-/--驱动的LUSC 基于这些新的观察结果，我们发现：1) PES/Trp53-/- 小鼠可以。从多个起源细胞发展出 LUSC 肿瘤，产生具有独特生物学、基因组和生化特性；2) 3q26 扩增子中的其他基因有助于 PES/Trp53-/--驱动的 LUSC 将通过设计的两个相互关联的具体目标进行测试。 1) 评估 PES/Trp53-/- 小鼠体内由 Club 和 AT2 细胞产生 LUSC 肿瘤的能力； 2) 确定来自不同细胞的 PES/Trp53-/--驱动的 LUSC 肿瘤的基因组和分子特征该补充项目是母基金目标 2 的重要延伸，该目标旨在表征来自 LBSC 的 PES/Trp53-/- 驱动的 LUSC 的新型 GEMM。家长资助：1) 评估替代来源细胞（Club 和 AT2 肺干细胞）在 LUSC 中的作用 2) 鉴定源自 LBSC、Club 的 LUSC 肿瘤的基因组和分子特征，和 AT2 肺干细胞；以及 3) 表征最近鉴定的 3q26 基因作为可能修饰因子的作用这些研究的完成将为生物异质性提供新的见解。在含有 3q26 CNG 的 LUSC 肿瘤中观察到，并鉴定可能的致癌信号通路和基因可用作 LUSC 肿瘤发生的生物标志物并作为治疗干预的靶点。