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.

我们的工作重点是控制协调细胞迁移和侵袭的细胞骨架动力学事件所需的细胞信号传导的重要蛋白质家族。这些是癌症进展到转移的根源的关键生物过程。我们的研究项目分为三个领域。首先，我们有兴趣获得分子网络和有助于细胞骨架动力学的分子机制的基础知识。这些研究工作重点关注 RAS 蛋白家族，例如 RHO 和 ARF 亚家族，并依靠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以及细胞迁移和侵袭的机制的重要发现。其次，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。我们发现上面研究的许多蛋白质调节称为细胞-细胞融合的基本生物过程。这包括 RHO 家族蛋白及其调节因子，以及许多辅助蛋白。这是一项核心生物功能，使我们肌肉的组成部分——成肌细胞能够将其细胞膜联合起来形成多核细胞。我们的努力利用分子、细胞和体内方法，目前集中于定义调节细胞融合的精确细胞骨架驱动机制。第三，我们开发了一种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以及小鼠模型的开发，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。我们的目标是尝试了解乳腺癌细胞在转移级联过程中的行为。这包括何时离开原发肿瘤并侵入次要器官，还包括它们如何整合并生存到新的外来环境中以形成微观或宏观转移。我们的工作将为信号网络提供重要的新的基本机制信息，从而有助于正常细胞生物学和癌症转移。需要这些知识来开发新的、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。