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

在肿瘤进展过程中，癌细胞经常失去其上皮细胞，并呈现间充质表型。这种上皮-间充质转化(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，人们知之甚少。一种人类乳腺上皮细胞系统，允许从一般上皮细胞群中分离出间充质亚群(R.A.温伯格实验室)。在那里，EMT与强烈增强的规范Wnt信号活性有关，并且需要强烈增强。我们发现EMT使细胞对顺铂治疗和紫外线(UV)照射具有抵抗力。这种差异反映在损伤的DNA和磷酸组蛋白2AX(GammaH2AX)的差异积累上。组蛋白脱乙酰酶抑制剂逆转了这种耐药表型。我们现在将试图回答以下问题：什么机制减少了顺铂诱导的DNA损伤在EMT反应下在乳腺上皮细胞和由此产生的癌症中的累积？是否可以通过拮抗Wnt活性和/或染色质重塑来克服EMT诱导的化疗耐药？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产生化疗耐药的机制，并有望勾勒出使耐药癌细胞重新敏感的策略。

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.