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PI3K Beta regulation of tumor metastasis

PI3K Beta 对肿瘤转移的调节

基本信息

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
项目类别：
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

项目摘要

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，了解介导转移的机制至关重要。重要的是，乳腺癌转移是由肿瘤和肿瘤之间的旁分泌和近分泌信号驱动的。基质细胞，例如巨噬细胞和血小板。在原发肿瘤中，巨噬细胞增强肿瘤细胞侵袭和内渗，在肺中，巨噬细胞增强肿瘤细胞的外渗、存活和生长。血小板在肿瘤转移中也发挥着重要作用，因为血小板可以保护循环肿瘤细胞免受免疫监视，诱导肿瘤细胞 EMT，并将中性粒细胞募集到转移部位。血小板也增强远端部位的肿瘤细胞粘附和外渗。该提案检验了 I 类 PI3K（PI3Kβ）是转移的关键调节因子的假设。选择性 PI3Kβ 抑制剂是可用的，但临床试验主要集中在 PTEN 缺失肿瘤的生长和尚未直接解决转移问题。我们发表的数据表明，肿瘤细胞中的 PI3Kβ 是侵袭和实验性转移。本次资助的新初步数据表明，巨噬细胞和血小板表达突变型 PI3Kβ 的突变体无法刺激肿瘤细胞中的多种促转移反应。重要的是，我们还表明，在小鼠体内对 PI3Kβ 进行药理抑制会导致体内肿瘤细胞外渗。该项目将直接测试PI3Kβ在转移中的作用。目标 1 检查 PI3Kβ 在近分泌中的作用以及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，体内肿瘤研究和活体成像。目标 2 检查 PI3Kβ 在血小板-肿瘤相互作用中的作用，重点关注血小板对肿瘤细胞信号传导和干性的调节。目标 3 将研究 PI3Kβ 在体内自发转移。我们将在肿瘤细胞、全球基质细胞中表达突变型 PI3Kβ，并且选择性地存在于巨噬细胞和血小板中。这些研究将使用活体成像和新型肺窗由核心 A 支持定义肿瘤细胞、巨噬细胞和血小板在治疗期间和治疗后的行为外渗。总之，这些研究将增进我们对 PI3Kβ 在肿瘤转移中的作用的理解，并提供支持 PI3Kβ 抑制剂治疗转移性疾病的重要临床前数据。