Chemoresistance as a consequence of Wnt-associated epithelial-mesenchymal transition

在肿瘤进展过程中，癌细胞经常失去上皮细胞并采用间充质表型。这种上皮-间质转化（EMT）涉及Wnt信号通路的激活。关于EMT如何影响肿瘤细胞对化疗的反应，我们知之甚少。人乳腺上皮细胞系统，允许从一般上皮细胞群分离间充质亚群（R. A. Weinberg实验室）。在那里，EMT与强烈增强的规范Wnt信号活动相关，并且需要这种活动。我们发现EMT使细胞对顺铂治疗和紫外线（UV）照射产生耐药性。这种差异反映在受损DNA和磷酸化组蛋白2AX （gammaH2AX）的不同积累上。组蛋白去乙酰化酶抑制剂逆转了这种抗性表型。我们现在将尝试回答以下问题：在EMT反应中，在乳腺上皮细胞及其衍生的癌症中，什么机制减少顺铂诱导的DNA损伤积累？emt诱导的化疗耐药能否通过拮抗Wnt活性和/或染色质重塑来克服？我们将使用Wnt信号的调节剂并评估它们的化学增敏作用。这项工作有望阐明EMT赋予化疗耐药的机制，并有望概述化疗耐药癌细胞再敏感化的策略。

During tumor progression, carcinoma cells frequently lose their epithelial and adopt a mesenchymal phenotype. This epithelial-mesenchymal transition (EMT) involves the activation of Wnt signaling pathways. Little is known about how EMT affects the response of tumor cells to chemotherapy. A system of human mammary epithelial cells, allows the isolation of a mesenchymal subset from a generally epithelial cell population (R. A. Weinberg lab). There, EMT is associated with and requires strongly enhanced canonical Wnt signaling activity. We found that EMT renders the cells resistant towards treatment with cisplatin, and also towards ultraviolet (UV) irradiation. The difference was reflected by differential accumulation of damaged DNA and phospho-histone 2AX (gammaH2AX). Histone deacetylase inhibitors reversed this resistance phenotype.We will now attempt to answer the following questions: What mechanisms reduce the accumulation of cisplatin-induced DNA damage in response to EMT, in mammary epithelial cells and cancers derived thereof? And could EMT-induced chemoresistance be overcome by antagonizing Wnt activity and/or chromatin remodeling? We will employ modulators of Wnt signaling and assess their chemosensitizing effects. This work is anticipated to clarify the mechanisms of chemoresistance conferred by EMT, and it will hopefully outline strategies to re-sensitize chemoresistant cancer cells.