应用光片层显微镜对上皮-间质转化及其在前列腺癌转移过程中作用的可视化研究

Metastasis is responsible for as much as 90% of cancer-associated mortality. A major model by which cancer cells are proposed to acquire invasive motility is the epithelial-mesenchymal transition (EMT). From a therapeutic standpoint, understanding the mechanisms of EMT and metastasis is important for preventing tumor dissemination in patients at high risk of developing metastatic lesions or to eradicate existing metastatic cancer cells in patients with more advanced disease. After years of extensive scientific discovery much has been learned about the networks that regulate EMT and metastasis, however, the dynamic process of EMT and metastasis is never directly observed at cellular resolution in vivo. In this study, we are trying to use light-sheet fluorescent microscopy to imaging this process and answer following key questions: 1. what is the relationship between EMT and metastasis; 2. which subpopulation cancer cells are most invasive; 3. are there specific niche environments that matters for EMT.

癌症转移是癌症致死的首要原因。上皮-间质转化（EMT）是癌细胞获得迁移和侵入能力的主要模型。对EMT及癌症转移机制的研究具有非常重要的临床意义。目前对EMT及癌症转移分子机制的研究虽然取得了巨大进展，但是仍然缺乏EMT导致癌症转移的直接在体证据。本项目的研究目标就是利用光片层荧光显微镜在3D培养的类器官中对EMT及癌症转移的动态过程进行实时观察，并解决以下关键科学问题：1.EMT对于癌转移是否是必须的？2.在原发肿瘤中哪种细胞是最具有侵入能力的？3.什么样的肿瘤微环境更有利于EMT的发生及癌细胞的侵袭？

前列腺癌是严重威胁到男性生存健康的一类恶性肿瘤。上皮-间质转化（EMT）被证明与癌症的远端转移、干细胞属性和耐药性密切相关。虽然已有许多研究揭示了上皮-间质转化的功能和分子机制，但对于在体内自发发生的上皮-间质转化过程，仍然知之甚少。PI3K/AKT和RAS/MAPK通路同时失调是转移性前列腺癌的特征，我们利用具有远端转移并伴随EMT的PI3K/AKT和RAS/MAPK共激活前列腺癌小鼠模型，确定了EMT过程中不同的肿瘤亚群，包括上皮细胞群(E)、间质细胞群(M)和划分为三个阶段的过渡状态EMT1/2/3细胞群。我们发现在EMT1阶段TGF-β信号通路的激活会导致EMT3阶段SNAIL1的上调表达。SNAIL通过决定细胞从EMT状态到M状态的转变来决定前列腺癌细胞向肝和肺的远端转移，但SNAIL在从E状态到EMT状态的转变过程中不发挥决定性的作用。在PI3K/AKT和RAS/MAPK共激活的病人样本中我们也发现了SNAIL1的高表达。该研究揭示了体内EMT的详细过程，并明确了前列腺癌临床相关的关键阶段和转录因子。