突变神经干细胞成瘤前竞争力与区域癌化的研究

Tumor formation is a process in which cell accumulates mutations and gains survival advantage. Adult stem cells were considered to be the cell of origin for tumors. Stem cells with genetic mutation will get competitiveness to form a morphologically normal region with genetic alteration, the phenomenon of which is called “field cancerization”. By utilizing previously established tumor suppressor NF1, P53 and PTEN based mouse malignant glioma model, we have demonstrated that the malignant gliomas originate from adult stem/progenitor cells. Neural stem/progenitor-specific deletion of tumor suppressors resulted in glioma formation in 6-13 months with 100% penetrance. However, the relationship between mutant and normal stem cells, stem cells and their niche during this process is still unknown. This project is based on previous in vivo data and in vitro microarray data, and will use the mouse models of gliomas and lineage tracing strategy to systematically investigate changes of competitiveness between mutant and normal neural stem/progenitor cells prior to tumor formation. We will also reveal the impact of age related stem cell niche deterioration on the competitiveness of mutant/normal stem/progenitor cells. In addition, we will elucidate the role of Ras-MAPK in stem cell competitiveness. The completion of the project will provide insights to early diagnosis and prevention of tumor.

肿瘤的形成是细胞逐渐积累突变和获得竞争力的一个漫长过程。成体干细胞被认为是肿瘤的可能细胞起源。带有突变的干细胞获得竞争优势从而形成区域带有基因突变但形态学正常的克隆增生，被称为“区域癌化”。 利用前期建立的基于抑癌基因NF1、P53和PTEN的小鼠胶质瘤模型，我们证明了恶性胶质瘤主要起源于神经干/祖细胞，神经干细胞特异的抑癌基因敲除在6-13个月以后100%导致恶性胶质瘤的发生。然而，在此过程中突变神经干细胞和正常神经干细胞以及干细胞巢的关系仍然不清楚。本项目在前期的体内数据和体外基因表达芯片的基础上，利用神经干细胞特异的可诱导的恶性胶质瘤小鼠模型，使用世系追踪的手段，从体内和体外角度系统研究成瘤前各个时期突变干细胞和正常干细胞的竞争力；揭示年龄增长导致干细胞巢恶化对干细胞竞争力的影响；并探索干预Ras-MAPK对干细胞竞争力和成瘤时间的影响，为肿瘤的预防和早期诊断治疗提供依据。

肿瘤的形成是细胞逐渐积累突变和获得竞争力的一个漫长过程。神经干细胞被认为是恶性胶质瘤的细胞起源。为了寻找在肿瘤形成早期促进神经干细胞竞争力，加速肿瘤形成的候选基因，我们针对小鼠和人的神经干细胞和脑瘤进行了包括基因组、转录组和临床数据等多方面的综合分析。从中找到了多个可能影响神经干细胞自我更新和增殖的候选基因并初步确定了他们的功能。我们还报导了一例早期低等级脑膜瘤向肺部转移的病例，基因组的分析发现转移瘤可能并不需要形成具有新的突变的克隆，这预示着即使是发生频率非常低的脑肿瘤外周转移，其实也可能不需要额外的突变或者筛选的过程，肿瘤的转移很可能在肿瘤形成的早期即可以发生。在项目执行过程中，我们一共发表了3篇SCI论文，总影响因子超过10。一共培养了3名硕士研究生和一名博士研究生。