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钙库操纵的钙内流（SOCE）在肿瘤侵袭和转移中的机制作用。在本研究计划中，我们重点关注SOCE在侵袭足形成，细胞外基质降解和黑色素瘤转移的调节中的作用。转移是造成超过90%的癌症相关死亡的原因，并且几乎没有可用于转移性癌症的治疗选择。转移性细胞的一个基本特征是增强的运动性和侵袭性，这有助于肿瘤细胞克服基底膜和周围组织施加的屏障。据信，肿瘤细胞使用侵袭伪足来协调侵袭和ECM降解。我们最近在黑色素瘤中的初步研究支持了一种模型，其中SOCE被局部激活以通过Ca 2 +-Pyk 2-Src途径启动侵袭足形成、ECM降解和转移。来自Aim 1的预期结果将定义侵袭足形成和3D黑色素瘤侵袭期间SOCE介导的Ca 2+信号的时空组织。由于Ca 2+在空间，时间和浓度上的复杂组织是Ca 2+动员的最关键方面，决定了Ca 2+信号的速度，特异性和鲁棒性，并且几乎没有关于肿瘤侵袭或转移期间Ca 2+信号传导的时空调节的报道，我们的预期结果将为播散性黑素瘤细胞中的Ca 2+动员带来重要的见解。Aim 2和3的成功完成将定义黑色素瘤侵袭和转移中的新SOCE-Pyk 2-Src通路，并为去调控的SOCE如何促进黑色素瘤进展提供新的线索。重要的是，我们将使用新的选择性SOCE阻断剂GSK-7975 A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。该研究的成功将为靶向SOCE通路干预黑色素瘤转移提供概念证据。

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.