MECHANISMS OF MOTILITY AND METASTASIS in BREAST CANCER

这项建议的主要目的是阐明乳腺癌细胞运动的新的分子机制，这些机制与癌症的转移或扩散有关。我们将研究两个基因的功能。我们认为(1)减少的随机运动(ROM)调节癌细胞的运动速度；(2)神经性Wiskott-Aldrich综合征蛋白(N-WASP)调节细胞运动的方向性成分。我们将把ROM和N-WASP的功能与活体肿瘤中胶原纤维的快速、直线行走和乳腺癌转移到肺部联系起来。乳腺癌细胞中的ROM将被抑制，我们预计细胞移动和转移的速度都会加快。因此，ROM作为转移的抑制因子发挥作用。然而，抑制N-WASP预计会损害细胞运动和转移的方向性。因此，N-WASP是肿瘤转移的促进剂。在这项工作完成后，将确定ROM和N-WASP对运动和转移的调节机制。这将促进针对ROM和N-WASP的生物靶向药物的开发，这些药物可以用于控制转移。此外，这些以运动途径为靶点的药物适合与以生存或生长等不同途径为靶点的药物联合治疗。这将显著提高疾病控制率或疾病部分或完全消退患者的比例。这项提案涉及国家健康优先事项--癌症和相关的国家研究优先事项--健康老龄化和富有成效的老龄化，从长远来看，我们将能够创造出新的、亟需的转移治疗方法。

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.