Cellular Signalling and Cancer Metastasis

细胞信号传导和癌症转移

• 批准号: CRC-2021-00161
• 负责人: Côté, JeanFrançois
• 金额: $ 14.57万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Canada Research Chairs
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=750685
• 关键词: Cellular; Signalling; Cancer; Metastasis

Our work focuses on important protein families that control cellular signalling required for the cytoskeletal dynamics events that orchestrate cell migration and invasion. The are key biological processes at the root of cancer progression to metastasis. Our research program is divided into 3 areas.First, we are interested to gain the fundamental knowledge of the molecular networks and the molecular mechanisms that contribute to cytoskeletal dynamics. These research efforts are focused on the RAS-family of proteins, such as the RHO and ARF subfamilies, and rely on proximity labeling approaches to reveal their interactomes at high-throughput. Combined with powerful functional studies, these efforts have led to important discoveries of mechanisms controlling cytoskeletal dynamics and cell migration and invasion.Second, we study the normal biological functions of these molecules such that we can better understand how they contribute to cancer progression. We have found that a number of the proteins studied above regulate a basic biological process known as cell-cell fusion. This includes RHO-family proteins and their regulators, and a number of their accessory proteins. This is a central biological function allowing to the building blocks of our muscles, the myoblasts, to unite their cellular membranes to form multi-nucleated cells. Our efforts exploit molecular, cellular and in vivo approaches, and are currently centered on defining the precise cytoskeletal-drive mechanisms regulating cell fusion.Third, we have developed a broad approach to study the cellular and molecular processes that contribute to breast cancer metastasis. This includes functional studies in breast cancer cells and the development of mouse models that can answer the contributions of our specific new genes to metastasis. We study the roles of kinases and cytoskeletal regulators. Our goal is to attempt to understand breast cancer cells behavior as they navigate through the metastatic cascade. This includes when leaving the primary tumours and invading secondary organs, but also how they integrate and survive into the new foreign environment to form micro- or macro-metastases.Our work will contribute important new basic mechanistic information on the signalling networks that contribute to normal cell biology and to cancer metastasis. This knowledge is needed to develop the new and much needed innovative therapies aiming at limiting cancer spreading, a serious health threat.

我们的工作重点是重要的蛋白质家族，控制细胞骨架动力学事件所需的细胞信号，协调细胞迁移和入侵。这是癌症进展到转移的根本的关键生物学过程。我们的研究计划分为三个方面。首先，我们有兴趣获得分子网络和分子机制的基础知识，有助于细胞骨架动力学。这些研究工作主要集中在RAS家族的蛋白质，如RHO和ARF亚家族，并依赖于邻近标记方法，以高通量揭示其相互作用组。结合强大的功能研究，这些努力导致了控制细胞骨架动力学和细胞迁移和侵袭的机制的重要发现。第二，我们研究这些分子的正常生物学功能，以便我们可以更好地了解它们如何促进癌症进展。我们已经发现，上面研究的一些蛋白质调节一个基本的生物学过程，称为细胞-细胞融合。这包括RHO家族蛋白及其调节剂，以及它们的许多辅助蛋白。这是一个中心的生物功能，允许我们的肌肉，成肌细胞的积木，团结他们的细胞膜，形成多核细胞。我们的工作利用分子，细胞和体内的方法，目前集中在定义精确的细胞驱动机制调节细胞融合。第三，我们已经开发了一个广泛的方法来研究有助于乳腺癌转移的细胞和分子过程。这包括乳腺癌细胞的功能研究和小鼠模型的开发，这些模型可以回答我们特定的新基因对转移的贡献。我们研究激酶和细胞骨架调节剂的作用。我们的目标是试图了解乳腺癌细胞在转移级联反应中的行为。这包括当离开原发性肿瘤和入侵的次级器官，而且他们如何整合和生存到新的外来环境，形成微观或宏观转移。我们的工作将有助于信号网络，有助于正常细胞生物学和癌症转移的重要新的基本机制信息。需要这些知识来开发新的和急需的创新疗法，旨在限制癌症扩散，这是一种严重的健康威胁。