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

项目摘要 摘要肺鳞状细胞癌(LUSC)是肺癌的主要亚型，约占全肺的30%。 癌症诊断。LUSC患者治疗反应差，复发率高， 预后。这一黯淡结果的一个主要原因是缺乏具有良好特征的LUSC致癌驱动因素 这可以作为治疗的靶点。我们已经确定伴随而来的3q26拷贝数增加(CNG)和 TP53缺失定义了大约90%的LUSC肿瘤中存在的基因改变2此外，我们已经确定了3 3q26癌基因，PRKCI，ECT2和SOX2，它们在遗传和生化上协同驱动LUSC肿瘤 形式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 LUSC肿瘤发生的活体改变1我们的GEMM允许可诱导的PrkCI、Ect2和 肺组织中SOX2和Trp53基因敲除(PES/TrP53-/-)。家长基金的具体目的是：1)评估 蛋白激酶Cι和蛋白激酶Cι效应通路的药理抑制剂对大鼠心肌细胞增殖的影响 PES/Trp53-/-驱动的LUSC；以及2)在我们的PES/Trp53-/-LUSC中肿瘤的发生和发展的特征 GEMM来自肺基本干细胞(LBSCs)，LUSC的主要来源细胞。有趣的是，另外两个地区性 肺干细胞(Club和肺泡II型(AT2)细胞)也可以作为LUSC.5-7的来源细胞。此外， 我们已经在重复的3q26扩增子中发现了其他可能在 PES/TrP53-/--驱动LUSC。基于这些新的观察结果，我们假设：1)PES/Trp53-/-小鼠可以 从多个来源的细胞发展成LUSC肿瘤，产生具有不同生物学特性的LUSC肿瘤， 基因组和生化特性；以及2)3q26扩增子内的其他基因有助于 PES/TrP53-/--驱动LUSC。这些假设将通过设计的两个相互关联的具体目标来检验 目的：1)评价PES/Trp53-/-小鼠体内从Club和AT2细胞中产生LUSC肿瘤的能力； 2)确定PES/TrP53-/-驱动的LUSC肿瘤的基因组和分子特征 起源。这一补充项目是家长赠款目标2的重要延伸，该目标2建议 从LBSC中鉴定一种由PES/Trp53-/-驱动的LUSC的新型GEMM。拟议的研究将扩大 父母资助：1)评估替代来源细胞(Club和AT2肺干细胞)在LUSC中的作用 肿瘤形成；2)鉴定起源于LBSC，Club， 和AT2肺干细胞；以及3)表征最近发现的3q26基因作为可能的修饰物的作用 LUSC肿瘤发生的研究。这些研究的完成将为生物异质性提供新的见解 在携带3q26 CNG的LUSC肿瘤中观察并确定可能 可作为LUSC肿瘤发生的生物标志物，并作为治疗干预的靶点。

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.