Atypical Angiogenic Mimicry During Collective Lung Cancer Invasion

肺癌集体侵袭过程中的非典型血管生成拟态

• 批准号: 10439630
• 负责人: Adam I. Marcus
• 金额: $ 34.97万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439630
• 关键词: 3-Dimensional; Address; Back; Biological Markers; Cancer Etiology; Cancer Patient; Cell Count; Cell Line; Cells; Cellular biology; Cessation of life; Data; Disease; Disseminated Malignant Neoplasm; Event; Extracellular Matrix; Fostering; Genomics; Heterogeneity; Histologic; Image; Individual; Invaded; Lead; Ligands; Lung; Lung Adenocarcinoma; Lung diseases; Malignant neoplasm of lung; Metastatic malignant neoplasm to brain; Molecular; Molecular Analysis; Molecular Profiling; Movement; Mus; Nature; Neoplasm Metastasis; Organoids; Pathway interactions; Patients; Pattern; Phenotype; Population; Prevalence; Primary Neoplasm; Publishing; Research; Resolution; Resources; Series; Shapes; Signal Pathway; Signal Transduction; Slice; Solid Neoplasm; Stream; Techniques; Testing; Tissues; Vascular Endothelial Growth Factors; Western Blotting; Width; angiogenesis; antagonist; base; brain tissue; cancer cell; cell population study; cell type; cohesion; ex vivo imaging; experimental study; genomic platform; genomic profiles; image guided; in vivo; insight; jagged1 protein; mimicry; mouse model; multiphoton imaging; notch protein; programs; recruit; spatiotemporal; therapeutic target; tool; transcriptome; translational impact; tumor; tumor initiation; tumor progression; virtual

Abstract Collective invasion is a major mode of metastasis observed in patients across most solid tumor types. How the collective invasion pack operates, communicates, and navigates as a single cohesive unit remains unclear. To address this, we published on an image-guided genomics platform to isolate any living cell(s) within a collective invasion pack, and expand the population for genomic and molecular analysis, a technique we termed Spatiotemporal Cellular & Genomic Analysis (SaGA). We used SaGA to deconstruct the collective invasion pack and dissect the molecular profiles of leader and follower cells invading as a hierarchical cohesive unit. To generate the collective invasion pack, leader and follower cells undergo a VEGF/Notch-based angiogenic mimicry program that promotes cell:cell cooperation and invasion that is similar, but not identical to angiogenesis. VEGF secreted by invasive leaders recruits proliferative followers into the collective pack; once the pack is formed, leader and follower cells undergo a Notch1-Dll4 cell patterning program that includes the Dll4 antagonist, Jagged-1 (Jag1). Based upon our published and preliminary data, we hypothesize that cooperative signaling among contiguous cells via Notch1 and its ligands are required to form the spatially dependent signaling events within the invasion pack. We propose that this fosters cell:cell cooperation and leads to increased metastatic efficiency. To test this, in Aim 1 we will define how atypical angiogenic mimicry via Notch1/Jag1/Dll4 signaling operates to spatially regulate cooperation and invasion. This would be a significant step forward in understanding how this pathway operates to maintain the collective invasion pack, drive metastasis, and facilitate ECM remodeling. In Aim 2, we use Jag1 as a lung cancer leader cell biomarker to isolate the first patient leader cells and probe atypical angiogenic mimicry. This allows us to define the metastatic potential and translational impact of this rare yet invasive population in lung cancer patients. Throughout, we leverage unique resources developed here including SaGA-derived cell lines, the first set of early and late-stage invading lung patient-derived organoids, ex vivo imaging, and a rare set of lung primary tumors with paired metastatic brain tissue. We speculate that these data will provide mechanistic insight into the atypical angiogenic mimicry program and translational value towards understanding lung cancer patient leader cell biology.

抽象的 集体入侵是大多数实体瘤类型的患者中观察到的一种主要转移方式。如何 集体入侵包在单个凝聚力单元中运行，通信和导航尚不清楚。到 解决这个问题，我们在图像引导的基因组学平台上发表了，以隔离集体中的任何活细胞 入侵包，并扩大种群以进行基因组和分子分析，这是我们所谓的一种技术 时空细胞和基因组分析（SAGA）。我们使用传奇来解构集体入侵包 并剖析了作为分层凝聚单元入侵的领导者和追随者细胞的分子谱。到 产生集体入侵包，领导者和追随者细胞经历基于VEGF/Notch的血管生成 促进细胞的模拟程序：类似但与血管生成相同的细胞合作和侵袭。 由侵入性领导人分泌的VEGF招募了集体包装的增生追随者；一旦包为 形成，领导者和追随者单元经历了包括DLL4拮抗剂， JAGGED-1（JAG1）。基于我们发布和初步数据，我们假设合作信号传导 在连续细胞中通过Notch1及其配体需要形成空间依赖的信号事件 在入侵包中。我们建议这种促进细胞：细胞合作并导致转移性增加 效率。为了测试这一点，在AIM 1中，我们将定义如何通过Notch1/Jag1/dll4信号传导非典型的血管生成模仿 运作以空间调节合作与入侵。这将是理解的重要一步 该途径如何运作以维持集体入侵包，驱动转移并促进ECM 重塑。在AIM 2中，我们将JAG1用作肺癌铅细胞生物标志物来隔离第一个患者领导者细胞 和探测非典型的血管生成模仿。这使我们能够定义转移的潜力和翻译影响 在肺癌患者中这种罕见但侵入性的人群中。在整个过程中，我们利用开发的独特资源 这里包括传奇的细胞系，第一组早期和晚期入侵肺衍生 器官，离体成像和一组罕见的肺原发性肿瘤，带有成对的转移性脑组织。我们 推测这些数据将提供有关非典型血管生成模仿程序和 旨在了解肺癌患者领导者细胞生物学的翻译价值。