Cellular Signalling and Cancer Metastasis

我们的工作集中在重要的蛋白质家族上，这些蛋白质家族控制细胞骨架动力学事件所需的细胞信号，这些事件协调细胞的迁移和入侵。这些都是癌症进展到转移的根源的关键生物学过程。我们的研究计划分为三个方面。首先，我们感兴趣的是获得分子网络的基础知识和有助于细胞骨架动力学的分子机制。这些研究工作集中在Ras蛋白家族，如Rho和ARF亚家族，并依靠邻近标记方法高通量揭示它们的相互作用。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入侵的机制的重要发现。第二，我们研究了这些分子的正常生物学功能，以便我们能够更好地了解它们如何促进癌症进展。我们发现，上面研究的一些蛋白质调节着一种称为细胞-细胞融合的基本生物过程。这包括Rho家族蛋白及其调节蛋白，以及它们的一些辅助蛋白。这是一种核心的生物功能，允许我们肌肉的组成部分--成肌细胞--将它们的细胞膜结合起来，形成多核细胞。我们的努力利用了分子、细胞和体内的方法，目前主要集中在定义调控细胞融合的精确的细胞骨架驱动机制。第三，我们开发了一种广泛的方法来研究导致乳腺癌转移的细胞和分子过程。这包括对乳腺癌细胞的功能研究，以及能够回答我们特定的新基因对转移的贡献的小鼠模型的开发。我们研究了激酶和细胞骨架调节因子的作用。我们的目标是试图了解乳腺癌细胞在转移级联过程中的行为。这包括离开原发肿瘤和侵入次级器官时，以及它们如何融入新的外来环境并存活以形成微观或宏观转移。我们的工作将为有助于正常细胞生物学和癌症转移的信号网络提供重要的新的基本机制信息。这些知识是开发新的、亟需的创新疗法所必需的，目的是限制癌症的传播，癌症是一种严重的健康威胁。

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.