Inhibiting tumor growth and metastasis in highly aggressive breast cancers with centrosome amplification

通过中心体扩增抑制高度侵袭性乳腺癌的肿瘤生长和转移

• 批准号: 10670436
• 负责人: Ozgur Sahin
• 金额: $ 33.2万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670436
• 关键词: 4T1; Acetylation; Apoptosis; Apoptotic; BCL2 gene; Binding Proteins; Biological Assay; Breast; Breast Cancer Model; Breast Cancer Patient; CDC2 gene; CRISPR/Cas technology; Cell Death; Cell Death Induction; Cell Line; Cell Polarity; Cell division; Cells; Centrosome; Clathrin; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Defect; Distant Metastasis; Experimental Models; Extracellular Matrix; Focal Adhesions; Genetic; Goals; Golgi Apparatus; Growth; HDAC2 gene; High Prevalence; Immunocompetent; Immunofluorescence Immunologic; In Vitro; Integrins; Interphase; Interphase Cell; Invaded; Knock-out; Legal patent; Lung; Malignant Neoplasms; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Methods; Microtubules; Mission; Mitosis; Mitotic; Mitotic spindle; Modeling; Molecular; Mouse Mammary Tumor Virus; Mutation; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Normal Cell; Organoids; Output; Ovarian; Patient-Focused Outcomes; Phenotype; Physiological; Primary Neoplasm; Prognosis; Prostate; Proteins; Public Health; Research; Role; TP53 gene; Testing; Therapeutic; Toxic effect; Transgenic Mice; Tubulin; Tumor-Derived; United States National Institutes of Health; Xenograft procedure; advanced breast cancer; aggressive breast cancer; cancer cell; cell motility; clinically relevant; disability; high risk; improved; in vivo; inhibitor; innovation; live cell imaging; malignant breast neoplasm; migration; mortality; mouse model; mutant; novel; overexpression; patient derived xenograft model; patient subsets; polarized cell; polyoma middle tumor antigen; pre-clinical; prevent; success; therapeutic target; three dimensional cell culture; trafficking; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

PROJECT SUMMARY Centrosome amplification (CA) is highly prevalent in cancer and strongly associated with tumor progression and worse prognosis in several different cancers, including breast, prostate, ovarian and lung. Centrosome amplified cells also demonstrate increased motility and invasiveness leading to metastasis. Moreover, CA is associated with genetic aberrations, such as p53 mutation that are commonly observed in aggressive forms of cancers, such as the triple negative breast cancer (TNBC). Our long-term goal is to target the growth and metastatic dissemination of aggressive breast tumors with CA that will ultimately lead to improved patient outcome. The overall objectives of this project are to (i) inhibit tumor growth in breast cancer models with CA via inducing centrosome de-clustering and formation of multipolar spindles upon targeting transforming acidic coiled-coil 3 (TACC3), and to (ii) block local invasion and metastatic dissemination in CA models by preventing cell polarization, migration and invasion upon inhibition of TACC3. The central hypothesis is that TACC3 inhibition will, on one hand, prevent active clustering of amplified centrosomes into two spindle poles during mitotic cell division leading to multipolar mitosis and apoptotic cell death in p53 altered cells, and on the other hand disrupts centrosome and Golgi re-orientation, microtubule nucleation and cell polarization in interphase cells leading to decreased migration. The rationale for this project is that TACC3 inhibition represents a unique opportunity to eliminate the most aggressive tumors that have supernumerary centrosomes, while sparing the normal cells. The central hypothesis will be tested by pursing two specific aims: 1.) To inhibit tumor growth in aggressive breast cancer models with CA by targeting TACC3, and 2.) To prevent metastasis in aggressive breast cancer models with CA by targeting TACC3. State-of-the-art experimental settings with translatable approaches will be employed, including tumor organoids, patient- derived xenografts and immunocompetent transgenic mouse model of advanced breast cancer that we characterized in terms of CA. The research proposed in this project is innovative as it aims to study mitosis/interphase-specific interactomes of TACC3 that are essential for TACC3-mediated cell division in mitotic cells and cell polarity in interphase cells that we propose to block using our novel and highly potent TACC3 inhibitor as well as using CRISPR-mediated knock-out. The proposed project is significant because it is expected to provide key mechanistic and phenotypic pre-clinical data to support the notion that targeting TACC3 concomitantly inhibits tumor growth and metastasis in breast cancer models with CA, which will then dramatically reduce mortality rates among patient subpopulation with highly aggressive cancers.

项目摘要 中心体扩增（CA）在癌症中高度普遍，并且与肿瘤进展密切相关 在几种不同的癌症中的预后较差，包括乳房，前列腺，卵巢和肺部。中心体 扩增的细胞还表现出增加的运动性和侵袭性导致转移。而且，CA是 与遗传像差有关，例如通常以侵略性形式观察到的p53突变 癌症，例如三重阴性乳腺癌（TNBC）。我们的长期目标是针对增长和 用CA转移侵袭性乳腺肿瘤的转移性传播，最终会导致患者改善 结果。该项目的总体目标是（i）抑制CA乳腺癌模型的肿瘤生长 通过诱导中心体的去聚类和多极纺锤的形成，靶向转化酸性 盘绕螺旋3（TACC3），以及（ii）通过CA模型阻止局部入侵和转移传播 防止细胞极化，迁移和侵袭TACC3。中心假设是 TACC3抑制作用将一方面防止将扩增的中心体的主动聚集到两个主轴杆中 在有丝分裂细胞分裂期间，导致多极有丝分裂和p53改变细胞的凋亡细胞死亡，并在 另一只手会破坏中心体和高尔基的重新定位，微管成核和细胞极化 相间细胞导致迁移减少。该项目的理由是TACC3抑制 代表了消除超级肿瘤的独特机会 中心体，同时保留正常细胞。中心假设将通过追求两个特定的 目的：1。）通过靶向tacc3抑制侵袭性乳腺癌模型中的肿瘤生长，而2。） 通过靶向TACC3，可以通过CA进行侵袭性乳腺癌模型的转移。最先进的 将采用具有可翻译方法的实验环境，包括肿瘤器官，患者 - 我们的晚期乳腺癌的异种移植物和免疫能力的转基因小鼠模型 以大约为特征。该项目提出的研究是创新的，因为它旨在研究 TACC3的有丝分裂/相间特异性相互作用，这对于Tacc3介导的细胞分裂至关重要 我们建议使用新颖且高度有效的相互作用细胞中的有丝分裂细胞和细胞极性 TACC3抑制剂以及使用CRISPR介导的淘汰赛。拟议的项目很重要，因为 预计它将提供关键的机械和表型前数据，以支持以下概念 TACC3同时抑制了具有CA的乳腺癌模型中的肿瘤生长和转移，然后将 高度侵略性癌症大大降低了患者亚群中的死亡率。