MECHANISMS OF MOTILITY AND METASTASIS in BREAST CANCER

本研究的主要目的是阐明与乳腺癌转移或扩散有关的乳腺癌细胞运动的新分子机制。两个基因的功能将被研究。我们提出：(1)减少的非随机运动（ROM）调节癌细胞的运动速度；(2)神经Wiskott-Aldrich综合征蛋白（N-WASP）调节细胞运动的方向成分。我们将把ROM和N-WASP的功能与活肿瘤中沿着胶原纤维的快速线性行走和乳腺癌向肺转移联系起来。乳腺癌细胞中的ROM会受到抑制，我们预计细胞运动和转移的速度都会加快。因此，ROM具有抑制肿瘤转移的功能。然而，抑制N-WASP可能会损害细胞运动和转移的方向性。因此，N-WASP是转移的启动子。在本工作完成后，将明确ROM和N-WASP对运动和转移的调控机制。这将有助于开发ROM和N-WASP的生物靶向药物，用于控制转移。此外，这些靶向运动途径的药物适合与靶向其他途径（如生存或生长）的药物联合治疗。这将显著提高疾病控制率或部分或完全疾病消退的患者比例。该提案解决了国家健康优先事项、癌症和相关的国家研究优先事项、健康老龄化和富有成效地老龄化，从长远来看，我们将能够为转移创造新的急需的治疗方法。

The broad aim of this proposal is to elucidate novel molecular mechanisms of breast cancer cell motility that are relevant to metastasis or the spread of cancer. The function of two genes will be studied. We propose that (1) reduced on-random motile (ROM) regulates the speed of cancer cell movement, and (2) Neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the directional component of cell movement. We will relate the function of ROM and N-WASP to rapid, linear walking along collagen fibres in live tumours and to breast cancer metastasis to the lung. ROM will be inhibited in breast cancer cells and we expect increases in both the speed of cell movement and metastasis. Therefore, ROM functions as a suppressor of metastasis. Inhibition of N-WASP, however, is expected to compromise both the directionality of cell movement and metastasis. N-WASP is therefore, a promoter of metastasis. At the completion of this work, the regulatory mechanisms of motility and metastasis by ROM and N-WASP will be defined. This will facilitate the development of biologically targeted agents for ROM and N-WASP that can be used to control metastasis. In addition, these agents that target the motility pathway are appropriate for use in combined therapy with agents that target a different pathway such as survival or growth. This will significantly improve disease control rates or the proportion of patients with partial or complete disease regression. This proposal addresses the National Health Priority, cancer, and related National Research Priority, ageing well and ageing productively, where in the longer term, we will be able to create new and much needed therapy for metastasis.