Role of phosphate availability in lung cancer invasion and bone metastasis

磷酸盐有效性在肺癌侵袭和骨转移中的作用

• 批准号: 10415838
• 负责人: Jamie Arnst
• 金额: $ 7.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415838
• 关键词: Address; Affect; Agar; Aggressive behavior; American diet; Automobile Driving; Behavioral Mechanisms; Bone Development; Breast; Cancer Model; Cancer cell line; Cause of Death; Cell Line; Cell-Matrix Junction; Cells; Consumption; Data; Development; Diagnosis; Diet; Endothelium; Exhibits; Fluorescence Resonance Energy Transfer; Food; Genes; Growth; Heterogeneity; Homing; In Vitro; Incidence; Individual; Intake; KRASG12D; Knowledge; Link; Luciferases; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metabolism; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Bone; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Osteolytic; Play; Process; Prognosis; Prostate; Risk Factors; Role; Serum; Signal Pathway; Site; Skeleton; Skin Carcinogenesis; Sodium; Testing; Time; Tumor Cell Invasion; Tumor Cell Migration; Tumor Tissue; Xenograft Model; angiogenesis; base; bone; bone turnover; cancer cell; cancer initiation; cell behavior; cell growth; cell motility; dietary; fracture risk; gibbon ape leukemia virus receptor; inorganic phosphate; lung cancer cell; lung xenograft; lymph nodes; migration; neoplastic cell; novel; pain reduction; prevent; response; sensor; symporter; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; underserved area; uptake

PROJECT SUMMARY Metastatic dissemination is a leading cause of death from cancer with metastasis to bone represents a particularly poor prognosis. Unfortunately, metastasis to bone is one of the most common sites of metastases in cancers such as breast, prostate and lung. In lung cancer, near half of advanced cases develop metastasis to the bone significantly impacting morbidity and survival. The underlying mechanisms are incompletely understood limiting treatment options to reducing pain and fracture risk after diagnosis. Therefore, studies addressing this underserved area would mark a significant advance in preventing and treating bone metastasis. Increasingly different components of the tumor microenvironment have been identified as modulators of cancer progression. Ourselves and others have identified one such component to be inorganic phosphate (Pi), which is elevated in the American diet due to processed foods. High dietary Pi has putatively been linked to cancer progression and aggression. Our data suggests that high Pi could increase local invasion, angiogenesis and bone turnover potentially driving tumor dissemination and priming the metastatic niche in bone. Further, using a FRET-based Pi sensor we have observed marked differences in cytosolic Pi levels within individual lung cancer cells. Suggesting that tumor cells have varying degrees to which they can sense and respond to changes in Pi levels. Thus, leading to the postulation that a subpopulation of tumor cells is more sensitive to fluctuations in Pi and as a result drive tumor progression and metastasis to the bone. Studies proposed herein will use a state-of-the-art mouse metastasis model and a fluorescent Pi sensor to monitor Pi metabolism in real-time to examine the role of phosphate availability in promoting lung cancer invasion and colonization of the bone. Specifically, we will test the hypothesis that high Pi availability in lung cancer is pro-invasion and pro-metastatic, and specifically influences the metastatic burden in the bone. Further, we will examine if heterogeneity in Pi transport within lung cancer cell lines promotes tumor cell homing to bone. To test this hypothesis, we will: 1) Determine if serum phosphate levels promote lung cancer invasion and bone metastasis and 2) Determine the cellular requirement of phosphate for tumor invasion and metastasis to bone. Results from the current proposal will provide new information about the role of Pi in altering cell behavior and mechanisms underlying tumor dissemination and colonization of the skeleton.

项目概要 转移性播散是癌症死亡的主要原因，其中骨转移代表了癌症死亡的主要原因。 预后特别差。不幸的是，骨转移是最常见的转移部位之一 乳腺癌、前列腺癌和肺癌等癌症。在肺癌中，近一半的晚期病例会发生转移 骨骼显着影响发病率和生存率。根本机制尚不完全清楚 限制治疗选择以减少诊断后的疼痛和骨折风险。因此，针对这一问题的研究 服务不足的地区将标志着预防和治疗骨转移的重大进步。日益 肿瘤微环境的不同成分已被确定为癌症进展的调节剂。 我们自己和其他人已经确定了其中一种成分是无机磷酸盐 (Pi)，它在 美国人的饮食习惯源于加工食品。高膳食 Pi 被认为与癌症进展有关 侵略。我们的数据表明，高 Pi 可以增加局部侵袭、血管生成和骨转换 潜在地驱动肿瘤扩散并启动骨中的转移生态位。此外，使用基于 FRET 的 Pi传感器我们观察到个体肺癌细胞内胞质Pi水平存在显着差异。 这表明肿瘤细胞可以不同程度地感知和响应 Pi 水平的变化。 因此，得出这样的假设：肿瘤细胞亚群对 Pi 的波动更敏感，并且 结果导致肿瘤进展并转移至骨骼。本文提出的研究将使用最先进的 小鼠转移模型和荧光Pi传感器实时监测Pi代谢以检查其作用 磷酸盐在促进肺癌侵袭和骨定植中的作用。具体来说，我们将测试 肺癌中高 Pi 利用率有利于侵袭和转移的假设，特别是 影响骨中的转移负荷。此外，我们将检查肺内 Pi 转运是否存在异质性 癌细胞系促进肿瘤细胞归巢至骨。为了检验这个假设，我们将： 1) 确定血清是否 磷酸盐水平促进肺癌侵袭和骨转移，2) 确定细胞需求 磷酸盐促进肿瘤侵袭和骨转移。当前提案的结果将提供新的 有关 Pi 在改变细胞行为和肿瘤传播机制中的作用的信息以及 骨骼的殖民化。