乳腺癌转移中EMT的示踪及分子调控机制

Breast cancer is the highest incidence of malignant tumors in women all over the world. Distant metastasis of the tumor is the main cause of the death of breast cancer. EMT has been invoked as a critical component of the metastatic process. However, recent studies report that carcinoma cells could metastasize without activating EMT programs. Whether EMT program is activated in vivo during tumor metastases remains controversial and elusive, as EMT process is complex and could also be partial, transient and reversible in nature. Using Kit-CreER and MMTV-PyMT mice, we reveal that whether Kit+ mammary epithelial cells contribute to lung metastases. We generate an innovative genetic tracing technology termed EMTracer to continuously track transient or partial EMT activity in vivo. This study provides direct genetic evidence of EMT in breast cancer metastases. By EMTracer system, we could study critical roles and molecular regulation mechanisms of the EMT transcription factors in tumor metastases. The newly established EMTracer transgenic model also provided us an opportunity to study the contribution of EMT to chemoresistance and molecular mechanisms.

乳腺癌是全世界女性发病率最高的恶性肿瘤。肿瘤远处转移是导致乳腺癌死亡的主要原因。上皮-间质转化（epithelial-mesenchymal transition，EMT）是乳腺癌细胞转移的关键步骤。最近的研究报道腺癌不激活EMT程序即可转移。由于EMT过程复杂，且具有局部、短暂和可逆的特点，在肿瘤转移期间体内是否激活了EMT过程仍有争议。我们利用转基因和乳腺癌模型小鼠揭示Kit+乳腺导管腔上皮细胞是否是乳腺原位癌和肺转移的细胞来源，为乳腺癌靶向治疗提供重要信息。我们建立了EMT遗传示踪新技术，能够连续不断地捕捉肿瘤转移过程中发生的EMT程序。为肿瘤转移中激活了EMT程序提供直接的遗传学证据。利用EMT示踪新系统，研究体内相关转录因子诱导的EMT在肿瘤转移中的功能及其分子调控机制，以及EMT促使肿瘤细胞对化疗药物产生抗药性的分子机制。

乳腺癌是全世界女性发病率最高的恶性肿瘤。肿瘤远处转移是导致乳腺癌死亡的主要原因。上皮-间质转化（epithelial-mesenchymal transition，EMT）是乳腺癌细胞转移的关键步骤。最近的研究报道腺癌不激活EMT程序即可转移。由于EMT过程复杂，且具有局部、短暂和可逆的特点，在肿瘤转移期间体内是否激活了EMT过程仍有争议。该项目开发了一个用于瞬时无缝追踪细胞遗传命运图谱系统，研究了从局部原发肿瘤到远处转移部位的体内EMT基因活性。在自发的乳腺癌肺转移模型中，发现原发性肿瘤细胞在原位激活了vimentin（波形蛋白）和N-cadherin（N-钙粘蛋白），但只有N-cadherin在转移过程中被激活。表达过N-cadherin的肿瘤细胞构成了大部分肺转移灶。为肿瘤转移中激活了EMT程序提供直接的遗传学证据。