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.

大多数人类癌症表现为上皮尖-基极性的丧失 良性到浸润性癌。心尖-基极通常被认为是对抗肿瘤的把关人 发展和转移。上皮-间充质转化(EMT)提供稳定的癌细胞 在转移过程中侵袭和传播的能力。尽管上皮细胞极性的丧失是一个早期步骤 在EMT过程中，很大程度上认为极性是EMT诱导信号的被动接受者 减少上皮特征。目前还很少知道心尖-基极是否会直接影响 EMT转录因子在肿瘤过程中作为反馈机制控制EMT进展 转移。这一建议侧重于理解心尖-基底极性调节的机制 机械直接作为EMT的关键检查点，阻止肿瘤的侵袭和转移。vbl.使用 具有完整顶端-基底端的小鼠和人上皮3D器官培养，我们的目标是1)阐明 顶端-基底极性阻止EMT和侵袭的分子机制；2)了解 PAR极性复合体调节EMT转录因子抑制EMT；3)确定参与 心尖-基底极性/EMT通路在体内和人乳腺癌侵袭转移中的作用 进步。