Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

基质硬度对肿瘤侵袭和转移的调节

• 批准号: 9315114
• 负责人: Jing Yang
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315114
• 关键词: Acinus organ component; Biochemical; Breast Cancer Patient; Cell Nucleus; Cells; Cues; Cytoplasm; Data; Development; Distant Metastasis; Embryo; Epithelial; Extracellular Matrix; Goals; Hardness; Human; Integrins; Link; Mammary Neoplasms; Mammary gland; Manuals; Mechanics; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Morphogenesis; Neoplasm Metastasis; Normal tissue morphology; Nuclear; Nuclear Translocation; Outcome; Palpation; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Play; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Transcription Factor 3; Translating; Tumor Cell Invasion; Work; Yang; cancer cell; clinically significant; epithelial to mesenchymal transition; in vivo; malignant breast neoplasm; malignant phenotype; mechanical force; mechanical properties; mechanotransduction; novel; programs; public health relevance; reconstitution; response; transcription factor; tumor; tumor microenvironment; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Breast tumors are often identified by manual palpation due to their apparent "hardness" compared to normal tissue. The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies show that increasing matrix stiffness can induce a malignant phenotype in cultured human mammary acini, suggesting that mechanical properties of extracellular matrix directly regulate tumor metastasis. However, how mechanical forces are translated into biochemical signals to promote tumor invasion and metastasis is largely unknown. Our preliminary studies found that rigid matrix stiffness activates a key developmental program termed Epithelial- Mesenchymal Transition (EMT) to promote tumor metastasis. We therefore hypothesize that mechanical forces regulate EMT-inducing transcription factors through a novel mechanotransduction pathway to promote tumor invasion and metastasis. To test this hypothesis, we plan to 1-2) dissect the molecular mechanism by which mechanical forces activate EMT-inducing transcription factors; 3) determine the involvement of mechanoregulation of EMT-inducing transcription factors in promoting metastasis in vivo and in predicting long-term survival in human breast cancer patients.

描述（由申请人提供）：与正常组织相比，乳腺肿瘤具有明显的“硬度”，因此通常通过手动触诊来识别。乳腺肿瘤中纤维化病灶的存在与组织硬度增加10-50倍相关，并与远处转移和不良结局相关。最近的研究表明，增加基质硬度可以诱导培养的人乳腺腺泡的恶性表型，这表明细胞外基质的机械性质直接调节肿瘤转移。然而，机械力如何转化为生化信号以促进肿瘤侵袭和转移在很大程度上是未知的。我们的初步研究发现，刚性基质硬度激活一个关键的发育程序，称为上皮-间充质转化（EMT），以促进肿瘤转移。因此，我们推测，机械力调节EMT诱导转录因子通过一种新的mechanotransduction途径，以促进肿瘤的侵袭和转移。为了验证这一假设，我们计划1-2）剖析机械力激活EMT诱导转录因子的分子机制; 3）确定EMT诱导转录因子的机械调节在促进体内转移和预测人类乳腺癌患者长期生存中的参与。