PI3K Beta regulation of tumor metastasis

PI3K Beta 对肿瘤转移的调节

• 批准号: 10408965
• 负责人: ANNE R BRESNICK
• 金额: $ 46.91万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408965
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Basement membrane; Binding; Biological; Biology; Blood Platelets; Breast Cancer Treatment; Breast cancer metastasis; Cell Adhesion; Cell Communication; Cell secretion; Cells; Clinical Trials; Coculture Techniques; Data; Disease; Distal; Endothelium; Extracellular Matrix; Extravasation; Future; Grant; Growth; Human; IL8 gene; Immune; Immunologic Surveillance; In Vitro; Invaded; Kinetics; Lung; MCF10A cells; Measures; Mediating; Metastatic Neoplasm to the Lung; Metastatic to; Mus; Mutant Strains Mice; Neoplasm Circulating Cells; Neoplasm Metastasis; Neutrophil Infiltration; PTEN gene; Paracrine Communication; Patients; Pharmacology; Platelet aggregation; Play; Primary Neoplasm; Process; Proteomics; Publishing; Regulation; Role; Signal Transduction; Signaling Protein; Site; Stromal Cells; Supporting Cell; Testing; Tumor Cell Invasion; Tumor-infiltrating immune cells; VEGFA gene; Wild Type Mouse; cancer therapy; experimental study; improved; in vivo; inhibitor; insight; intravital imaging; knockin animal; lung imaging; macrophage; malignant breast neoplasm; migration; mortality; mutant; neoplastic cell; novel; paracrine; pre-clinical; recruit; response; stemness; tumor; tumor behavior; tumor growth

To improve treatments for breast cancer, it is critical to understand the mechanisms mediating metastasis. Importantly, breast cancer metastasis is driven by paracrine and juxtacrine signaling between tumor and stromal cells, such as macrophages and platelets. In the primary tumor, macrophages enhance tumor cell invasion and intravasation, and in the lung, macrophages enhance tumor cell extravasation, survival and growth. Platelets also play a major role in tumor metastasis, as platelets protect circulating tumor cells from immune surveillance, induce tumor cell EMT, and recruit neutrophils to the metastatic site. Platelets also enhance tumor cell adhesion and extravasation at distal sites. This proposal examines the hypothesis that the Class I PI3K, PI3Kβ, is a key regulator of metastasis. Selective inhibitors of PI3Kβ are available, but clinical trials have largely focused on the growth of PTEN-null tumors and have not directly addressed metastasis. Our published data show that PI3Kβ in tumor cells is required for invasion and experimental metastasis. New preliminary data in this grant show that macrophages and platelets expressing mutant PI3Kβ are defective for stimulating a variety of pro-metastatic responses in tumor cells. Importantly, we also show that pharmacological inhibition of PI3Kβ in mice causes a dramatic reduction in tumor cell extravasation in vivo. This project will directly test the role of PI3Kβ in metastasis. Aim 1 examines the role of PI3Kβ in juxtracrine and paracrine signaling between tumor cells and macrophages, using in vitro co-culture experiments, in vivo tumor studies, and intravital imaging. Aim 2 examines the role of PI3Kβ in platelet-tumor interactions, focusing on platelet modulation of tumor cell signaling and stemness. Aim 3 will study the role of PI3Kβ during spontaneous metastasis in vivo. We will express mutant PI3Kβ in tumor cells, globally in stromal cells, and selectively in macrophages and platelets. These studies will use intravital imaging and a novel lung window supported by Core A to define the behavior of tumor cells, macrophages and platelets during and after extravasation. Together, these studies will advance our understanding of the role of PI3Kβ in tumor metastasis, and provide important preclinical data supporting the use of PI3Kβ inhibitors for metastatic disease.

为了改善乳腺癌的治疗方法，了解介导转移的机制至关重要。 重要的是，乳腺癌转移是由旁分泌和近距离信号驱动的 基质细胞，例如巨噬细胞和血小板。在原发性肿瘤中，巨噬细胞增强肿瘤细胞 入侵和侵入，在肺中，巨噬细胞增强了肿瘤细胞的渗出，存活和 生长。血小板在肿瘤转移中也起着重要作用，因为血小板可保护循环肿瘤细胞免受 免疫监测，诱导肿瘤细胞EMT并募集中性粒细胞到转移性部位。血小板也是 增强肿瘤细胞粘合剂和脱落位点的渗出。 该提案研究了以下假设：I级PI3KPI3Kβ是转移的关键调节剂。选择性 PI3Kβ的抑制剂可用，但是临床试验主要集中在Pten-null肿瘤的生长上 尚未直接解决转移。我们发表的数据表明，肿瘤细胞中的PI3Kβ需要 入侵和实验转移。这笔赠款中的新初步数据表明巨噬细胞和血小板 表达突变体PI3Kβ对于刺激肿瘤细胞中各种促旋转反应的有缺陷。 重要的是，我们还表明，PI3Kβ在小鼠中的药物抑制作用会导致急剧减少 体内肿瘤细胞渗出。 该项目将直接测试PI3Kβ在转移中的作用。 AIM 1考试PI3Kβ在Juxtracrine中的作用 肿瘤细胞和巨噬细胞之间的旁分泌信号传导，使用体外共培养实验，体内 肿瘤研究和浸润成像。 AIM 2考试PI3Kβ在血小板肿瘤相互作用中的作用，聚焦 关于肿瘤细胞信号传导和干性的血小板调节。 AIM 3将研究PI3Kβ在 体内自发转移。我们将在肿瘤细胞中，全球在基质细胞中表达突变体PI3Kβ，以及 有选择地在巨噬细胞和血小板中。这些研究将使用插入式成像和新颖的肺部窗口 由核心A支持以定义肿瘤细胞，巨噬细胞和血小板的行为 奢侈。总之，这些研究将促进我们对PI3Kβ在肿瘤转移中的作用的理解， 并提供重要的临床前数据，以支持PI3Kβ抑制剂用于转移性疾病。