Store-Operated Calcium Entry in Tumor Invasion and Metastasis

项目摘要 我们的长期目标是确定钙库操纵的钙内流（SOCE）在肿瘤侵袭中的机制作用 和转移。在本研究计划中，我们重点关注SOCE在invadopodium调控中的作用 形成、细胞外基质降解和黑色素瘤转移。肿瘤转移导致的 90%的癌症相关死亡，转移性癌症的治疗选择很少。一个基本 转移性细胞的特征是增强的运动性和侵袭性，这有助于肿瘤细胞克服 由基底膜和周围组织形成的屏障。据信肿瘤细胞利用 入侵伪足协调入侵和ECM降解。我们最近对黑色素瘤的初步研究 支持SOCE被局部激活以启动侵袭伪足形成、ECM降解和 通过Ca 2 +-Pyk 2-Src途径转移。Aim 1的预期结果将定义空间-时间 SOCE介导的Ca 2+信号在侵袭足形成和3D黑色素瘤侵袭期间的组织。以来 Ca 2+在空间、时间和浓度上的复杂组织是Ca 2+最关键的方面 动员，决定速度，特异性和稳健性的Ca 2+信号，几乎没有 报道了在肿瘤侵袭或转移过程中Ca 2+信号的时空调节，我们的预期 结果将带来重要的见解钙+动员在传播黑色素瘤细胞。成功 目标2和3的完成将定义黑色素瘤侵袭和转移中的新SOCE-Pyk 2-Src途径 并揭示了解除管制的SOCE如何促进黑色素瘤进展。重要的是，我们将使用新的 选择性SOCE阻断剂GSK-7975 A抑制人黑色素瘤单细胞侵袭和转移 直接从转移性黑色素瘤患者分离的悬浮液。拟议研究的成功将 为靶向SOCE途径干预黑色素瘤转移提供了概念证明。

PROJECT SUMMARY 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 invadpodium 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.