Store-operated calcium entry in tumor invasion and metastasis

肿瘤侵袭和转移中钙库操纵的钙进入

• 批准号: 9292921
• 负责人: Shengyu Yang
• 金额: $ 27.58万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-03 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9292921
• 关键词: Accounting; Actins; Arthritis; Atherosclerosis; Basement membrane; Calcium; Calcium Channel; Cell membrane; Cells; Cessation of life; Characteristics; Data; Development; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Extracellular Matrix; Extracellular Matrix Degradation; Fluorescence Resonance Energy Transfer; Goals; Health; Human; Image; Immunologic Surveillance; Integrins; Intervention; Knowledge; Light; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Microscopy; Modeling; Molecular; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Physiological; Primary Neoplasm; Recruitment Activity; Regulation; Reporting; Research; Resected; Role; STIM1 gene; Signal Transduction; Specificity; Specimen; Speed; Suspension substance; Suspensions; System; Testing; Time; Tissues; Tumor Cell Invasion; Work; Xenograft procedure; bone; cancer cell; cell motility; in vivo; inhibitor/antagonist; insight; live cell imaging; melanoma; mouse model; neoplastic cell; novel; research study; sensor; success; tumor

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.

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 在调节侵入伪足形成、细胞外基质降解和黑色素瘤转移中的作用。超过 90% 的癌症相关死亡是由转移造成的，而针对转移性癌症的治疗选择很少。转移细胞的一项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。据信肿瘤细胞利用侵袭伪足来协调侵袭和 ECM 降解。我们最近对黑色素瘤的初步研究支持一个模型，即 SOCE 被局部激活，通过 Ca2+-Pyk2-Src 途径启动侵袭伪足形成、ECM 降解和转移。 Aim1 的预期结果将定义 SOCE 介导的 Ca2+ 信号在侵袭足形成和 3D 黑色素瘤侵袭过程中的时空组织。由于Ca2+在空间、时间和浓度上的复杂组织是Ca2+动员的最关键方面，决定了Ca2+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过程中Ca2+信号的时空调节的报道，因此我们预期的结果将为播散性黑色素瘤细胞中Ca2+动员带来重要的见解。目标 2 和 3 的成功完成将在黑色素瘤侵袭和转移中定义一条新的 SOCE-Pyk2-Src 通路，并为解除管制的 SOCE 如何促进黑色素瘤进展提供新的线索。重要的是，我们将使用新型选择性 SOCE 阻断剂 GSK-7975A 来抑制直接从转移性黑色素瘤患者中分离的人黑色素瘤单细胞悬浮液的侵袭和转移。拟议研究的成功将为针对 SOCE 途径干预黑色素瘤转移提供概念证明。