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

项目总结 中心体扩增(CA)在癌症中非常普遍，并与肿瘤的进展密切相关 在几种不同的癌症中预后更差，包括乳腺癌、前列腺癌、卵巢癌和肺癌。中心体 扩增的细胞也表现出更强的运动性和侵袭性，从而导致转移。此外，CA是 与遗传异常有关，例如通常以侵袭性形式观察到的p53突变 癌症，如三重阴性乳腺癌(TNBC)。我们的长期目标是实现增长和 伴有CA的侵袭性乳腺肿瘤的转移转移最终将导致患者病情改善 结果。该项目的总体目标是(I)用CA抑制乳腺癌模型中的肿瘤生长 通过靶向转化酸性诱导中心体解聚和多极纺锤体的形成 螺旋线圈3(TACC3)，并通过(Ii)阻断CA模型的局部侵袭和转移 通过抑制TACC3，防止细胞极化、迁移和侵袭。中心假设是 一方面，抑制TACC3将阻止扩增的中心体活跃地聚集成两个纺锤体极点 在有丝分裂过程中，p53改变的细胞导致多极有丝分裂和凋亡细胞死亡，以及 另一方面破坏中心体和高尔基体重定向、微管成核和细胞极化。 间期细胞导致迁移减少。这个项目的基本原理是TACC3抑制 代表着一个独特的机会来消除最具侵袭性的肿瘤，这些肿瘤有多余的 中心体，而不是正常细胞。核心假设将通过追求两个具体的 目标：1.)通过靶向TACC3，抑制CA侵袭性乳腺癌模型中的肿瘤生长。 通过靶向TACC3来预防CA侵袭性乳腺癌模型中的转移。最先进的 将采用可翻译方法的实验环境，包括肿瘤器官、患者- 衍生异种移植和免疫活性转基因晚期乳腺癌小鼠模型的建立 以CA为特征的。本项目提出的研究具有创新性，因为它的目的是研究 TACC3的有丝分裂/间期特异性相互作用对TACC3介导的细胞分裂是必不可少的 有丝分裂细胞和间期细胞中的细胞极性，我们建议使用我们的新的和高效的 TACC3抑制剂以及使用CRISPR介导的基因敲除。拟议的项目意义重大，因为 预计它将提供关键的机制和表型临床前数据，以支持靶向的概念 在CA乳腺癌模型中，TACC3同时抑制肿瘤生长和转移，从而 显著降低高度侵袭性癌症患者亚群的死亡率。

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.