The Involvement of Epithelial-Mesenchymal Transition in Squamous Cell Carcinoma in vivo

项目摘要 我一直在开发我的论文项目在癌症进展的异质性。迄今为止，大多数研究使用 癌症模型，导致肿瘤起源于同质起源，然后分析表型， 下游分子的后果。然而，癌症是一种异质性疾病，甚至在一个单一的 在肿瘤中，由于肿瘤微环境的异质性，癌细胞的增殖潜力不同， 以及基因组的不稳定性。我计划利用这些可变性来获得对癌症的新见解。 皮肤作为人体最大、最外部的器官，极易受到致突变性、毒性和致病性的影响 侮辱。这种细胞损伤的有害结果是鳞状细胞癌的发展， 表皮的鳞状上皮细胞。绝大多数鳞状细胞癌是可以治愈的 如果早期发现;然而，在预后不良的鳞状细胞癌转移变得越来越多， 致命的上皮间充质转化（EMT），上皮细胞发育间充质细胞的过程。 表型通过失去极性和粘附在交换获得流动性和干性。的 EMT的生理意义不仅是重要的发育事件，如原肠胚形成， 神经嵴的形成，而且还与生理反应如伤口愈合和病理过程如 器官纤维化和癌症。它与将静止的上皮肿瘤细胞转化为运动的上皮肿瘤细胞有关。 恶性间充质细胞导致侵袭和转移。 肿瘤起始SCC细胞的子集接收TGFβ信号。这些细胞变得具有侵袭性并经历EMT。 我推测，在这个阶段，这些TGFβ反应性EMT转化细胞具有独特的“分子”结构， 这是一个与肿瘤发生的早期阶段不同的“特征”，并为它们的侵袭性，潜在的 转移特性。识别这些转录变化可能会导致新的药物靶点，减少 通过抑制癌细胞侵袭来减轻SCC的严重程度。在这个建议中，我概述了一个计划：（1）定义 TGFβ信号下游的转录变化作为良性肿瘤起始细胞进展为SCC癌 干细胞(2)开发一种EMT特异性报告器，使我能够监测侵袭性SCC肿瘤细胞， 经历EMT并定义区分该过程的转录签名。(3)设计和开发 CRISR/CAS介导的技术选择性靶向消融肿瘤启动的EMT候选基因 细胞，并确定I是否可以阻断SCC进展和/或转移。如果成功， 我的研究将阐明EMT的组成部分，这些组成部分是侵入性所必需的， 用于治疗或预防癌症的这种恶性状态的治疗靶点。

Project Summary I have been developing my thesis project on the heterogeneity of cancer progression. To date, most studies use cancer models that result in tumors stemming from a homogenous origin and then analyze the phenotype or downstream molecular consequences. However, cancer is a heterogeneous disease and even within a single tumor, the cancer cells vary in their proliferative potential due to heterogeneity in the tumor microenvironment as well as genome instability. I plan to exploit these variabilities to gain new insights into cancer. The skin as the body's largest and most external organ is highly susceptible to mutagenic, toxic, and pathogenic insults. A deleterious result of this cellular damage is the development of squamous cell carcinoma, which arises from the squamous epithelial cells of the epidermis. The vast majority of squamous cell carcinomas can be cured if detected early; however, upon poor prognosis squamous cell carcinoma metastasizes becoming ever more lethal. Epithelial mesenchymal transition (EMT), a process by which epithelial cells develop a mesenchymal phenotype through the loss of polarity and adhesion in exchange gaining mobility and stemness. The physiological significance of EMT is not only to the important developmental events such as gastrulation and neural crest formation, but also to physiologic responses such wound healing and pathologic processes such as organ fibrosis and cancer. It has been implicated in converting stationary epithelial tumor cells into motile malignant mesenchymal cells leading to invasion and metastasis. A subset of tumor-initiating SCC cells receive a TGFβ signal. These cells become invasive and undergo an EMT. I hypothesize that at this stage these TGFβ-responding EMT-transitioning cells have a unique “molecular signature” that is distinct from earlier stages in tumorigenesis, and holds clues to their invasive, potentially metastatic properties. Identifying these transcriptional changes could lead to novel drug targets that reduce the severity of SCCs by inhibiting cancer cell invasion. In this proposal, I outline a plan to: (1) Define the transcriptional changes downstream of TGFβ signaling as benign tumor-initiating cells progress to SCC cancer stem cells. (2) Develop an EMT-specific reporter that will allow me to monitor invasive SCC tumor cells as they undergo an EMT and define the transcriptional signature that distinguishes this process. (3) Devise and exploit CRISR/CAS-mediated technology to selectively target the ablation of EMT candidate genes in tumor-initiating cells and determine whether I can block SCC progression and/or metastasis as a consequence. If successful, my research will elucidate the components of EMT that are required for invasiveness and reveal potential therapeutic targets for the treatment or prevention of this malignant state of cancer.