Store-operated calcium entry in tumor invasion and metastasis

描述(由申请人提供)：我们的长期目标是确定存储操作的钙内流(SOCE)在肿瘤侵袭和转移中的机制作用。在这项研究计划中，我们重点研究SOCE在调节英多糖钠的形成、细胞外基质降解和黑色素瘤转移中的作用。转移是癌症相关死亡的90%以上的原因，转移性癌症的治疗选择很少。转移细胞的一个基本特征是运动性和侵袭性增强，这有助于肿瘤细胞克服基底膜和周围组织施加的障碍。据认为，肿瘤细胞利用侵袭足来协调侵袭和ECM降解。我们最近对黑色素瘤的初步研究支持这样一个模型，即SOCE被局部激活，通过钙-Pyk2-Src途径启动内陷形成、ECM降解和转移。来自Aim1的预期结果将定义在不孕症形成和3D黑色素瘤侵袭过程中SOCE介导的钙信号的时空组织。由于钙离子在空间、时间和浓度上的错综复杂的组织是钙离子动员最关键的方面，它决定了钙离子信号的速度、特异性和稳健性，而且几乎没有关于钙离子信号在肿瘤侵袭或转移过程中的时空调节的报道，我们预期的结果将为钙离子动员在黑色素瘤细胞扩散中带来重要的启示。目标2和3的成功完成将定义一个新的黑色素瘤侵袭和转移中的SOCE-Pyk2-Src通路，并为了解非调控的SOCE如何促进黑色素瘤的进展提供新的线索。重要的是，我们将使用新型选择性SOCE阻滞剂GSK-7975A来抑制直接从转移性黑色素瘤患者分离的人黑色素瘤单细胞悬液的侵袭和转移。这项研究的成功将为靶向SOCE途径干预黑色素瘤转移提供一个概念证明。

DESCRIPTION (provided by applicant): Our long term goal is to define the mechanistic roles of store-operated calcium entry (SOCE) in tumor invasion and metastasis. In this research plan we focus on the role of SOCE in the regulation of invadopodium formation, extracellular matrix degradation and melanoma metastasis. Metastasis is responsible for more than 90% of cancer-related death and there are few treatment options available for metastatic cancer. One essential characteristic for metastatic cells is enhanced motility and invasiveness, which helps tumor cells to overcome barriers imposed by basement membrane and surrounding tissues. It is believed that tumor cells use invadopodia to co-ordinate invasion and ECM degradation. Our recent preliminary studies in melanoma support a model whereby SOCE is locally activated to initiate invadopodium formation, ECM degradation and metastasis through a Ca2+-Pyk2-Src pathway. The expected results from Aim1 will define the spatio-temproal organization of SOCE-mediated Ca2+ signals during invadopodium formation and 3D melanoma invasion. Since the intricate organization of Ca2+ in space, time and concentration is the most critical aspect of Ca2+ mobilization that determines the speed, specificity and robustness of Ca2+ signals, and there is virtually no report on the spatio-temporal regulation of Ca2+ signaling during tumor invasion or metastasis, our anticipated results will bring significant insights into Ca2+ mobilization in disseminating melanoma cells. The successful completion of Aim 2 and 3 will define a novel SOCE-Pyk2-Src pathway in melanoma invasion and metastasis and shed new lights on how deregulated SOCE promote melanoma progression. Importantly, we will use novel selective SOCE blocker GSK-7975A to inhibit the invasion and metastasis of human melanoma single cell suspensions directly isolated from patients with metastatic melanoma. The success of the proposed study will provide a proof of concept for targeting SOCE pathway to intervening melanoma metastasis.