Apical-basal polarity in tumor progression and metastasis

肿瘤进展和转移中的顶底极性

• 批准号: 10677660
• 负责人: Jing Yang
• 金额: $ 37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10677660
• 关键词: 3-Dimensional; Apical; Benign; Breast Cancer Patient; Carcinoma; Cell Polarity; Cells; Characteristics; Complex; Data; Development; Distant Metastasis; E-Cadherin; Epithelial Cells; Epithelium; Family; Feedback; Gatekeeping; Goals; Human; Invaded; Link; Maintenance; Malignant Epithelial Cell; Mammary Neoplasms; Mediating; Mesenchymal; Molecular; Mus; Neoplasm Metastasis; Organoids; PARD6A gene; Pathway interactions; Phosphorylation; Play; Post-Translational Regulation; Process; Proteins; Research; Role; Series; Signal Induction; Testing; Tissues; Tumor Cell Invasion; Tumor Promotion; Ubiquitin; Ubiquitination; Work; atypical protein kinase C; breast cancer progression; epithelial to mesenchymal transition; experimental study; in vivo; novel; programs; protein degradation; transcription factor; tumor; tumor progression; tumor xenograft; ubiquitin-protein ligase

The majority of human carcinomas show loss of epithelial apical-basal polarity during the progression from benign to invasive carcinoma. Apical-basal polarity is often regarded as a gatekeeper against tumour development and metastasis. Epithelial-Mesenchymal Transition (EMT) provides stationary carcinoma cells the ability to invade and disseminate during metastasis. Although loss of epithelial cell polarity is an early step during the EMT process, polarity is largely thought to be a passive recipient of the EMT-inducing signals to decrease epithelial characteristics. Very little is known whether apical-basal polarity could directly impinge on the EMT transcription factors to function as feedback mechanisms to control EMT progression during tumor metastasis. This proposal focuses on understanding the mechanism by which apical-basal polarity regulatory machinery directly functions as a critical checkpoint of EMT to block tumor invasion and metastasis. Using mouse and human epithelial 3D organoid cultures with intact apical-basal polarity, we aim to 1) To elucidate the molecular mechanism by which apical-basal polarity blocks EMT and invasion; 2) To understand how the PAR polarity complex regulates EMT transcription factors to inhibit EMT; 3) To determine the involvement of the apical-basal polarity/EMT pathway in invasion and metastasis in vivo and in human breast cancer progression.

大多数人癌显示在从 对侵入性癌的良性。顶端极性通常被视为针对肿瘤的守门人 发展和转移。上皮间质转变（EMT）提供固定的癌细胞 在转移期间入侵和传播的能力。尽管上皮细胞极性的丧失是早期的一步 在EMT过程中，极性在很大程度上被认为是EMT诱导信号的被动接受者 降低上皮特征。知之甚少 EMT转录因子充当反馈机制，以控制肿瘤期间的EMT进展 转移。该提案的重点是理解顶端极性调节的机制 机械直接充当EMT的关键检查点，可阻止肿瘤侵袭和转移。使用 小鼠和人类上皮3D器官培养具有完整的顶碱极性，我们的目的是1）阐明 顶端极性阻止EMT和侵袭的分子机制； 2）了解如何 极性复合物调节EMT转录因子抑制EMT； 3）确定参与 体内和人类乳腺癌的侵袭和转移中的顶端极性/EMT途径 进展。