Regulation of Tumor Invasion and Metastasis by Matrix Stiffness
Regulation of Tumor Invasion and Metastasis by Matrix Stiffness
批准号:
10599661
负责人:
Jing Yang
金额:
$3.74万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
未结题
起止时间:
2015-08-01 至 2027-01-31
关键词:
BiochemicalDistant MetastasisEpithelialExtracellular MatrixHardnessHumanLYN geneMammary NeoplasmsManualsMesenchymalMolecularNeoplasm MetastasisNormal tissue morphologyNuclear TranslocationOrganoidsOutcomePalpationPathway interactionsPhosphotransferasesRegulationResearchSignal TransductionTWIST1 geneTestingTissuesTranslatingTumor Cell InvasionWorkbreast cancer progressionin vivomalignant phenotypemammarymechanical forcemechanical propertiesmechanotransductionnovelpreventtranscription factortumortumor microenvironment
中文摘要
摘要/摘要
乳腺肿瘤通常通过手工触诊来识别,因为与正常相比,乳腺肿瘤明显的“硬”。
组织。乳腺肿瘤中纤维性病灶的出现与组织增加10-50倍有关。
僵硬与远处转移和不良预后相关。最近的研究表明,增加矩阵
僵硬可以诱导培养的人乳腺器官的恶性表型,这表明
细胞外基质的力学性质直接调节肿瘤的转移。然而,有多机械
力量被转化为促进肿瘤侵袭和转移的生化信号在很大程度上是未知的。
我们的初步研究发现,刚性基质僵硬激活了一种新的机械转导途径
诱导上皮间充质转化(EMT),促进肿瘤转移。因此,我们假设
机械力激活Lyn激酶,允许EMT诱导的转录因子Twist1
促进肿瘤侵袭转移。为了验证这一假说,我们计划1)阐明分子
高组织硬度激活一种新的机械转导级联促进Twist1的机制
核移位与EMT;2)阐明软基质僵硬的新分子机制
防止Twist1核转位并抑制EMT;3)确定Twist1的参与
机械转导途径在促进体内转移和预测乳腺癌中的作用
进步。
英文摘要
Summary/Abstract
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 organoids, 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 novel mechanotransduction pathway to
induce Epithelial-Mesenchymal Transition (EMT) and promote tumor metastasis. We therefore hypothesize
that mechanical forces activates the LYN kinase to allow the EMT-inducing transcription factor TWIST1 to
promote tumor invasion and metastasis. To test this hypothesis, we plan to 1) To elucidate the molecular
mechanism by which high tissue stiffness activates a novel mechanotransduction cascade to promote TWIST1
nuclear translocation and EMT; 2) To elucidate the novel molecular mechanism by which soft matrix stiffness
prevents TWIST1 nuclear translocation and inhibit EMT; 3) To determine the involvement of the Twist1
mechanotransduction pathway in promoting metastasis in vivo and in predicting human breast cancer
progression.
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