Project 1: Tumor Microenvironment Initiators of the Metastatic Cascade in High-Risk Prostate Cancer

项目1：高危前列腺癌转移级联的肿瘤微环境启动因素

• 批准号: 10555400
• 负责人: Joshua Michael Lang
• 金额: $ 38.86万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555400
• 关键词: 3-Dimensional; Adjuvant Study; Androgen Receptor; Biological; Biological Markers; Biological Models; Cancer and Leukemia Group B; Cell Differentiation process; Cell Proliferation; Cells; Clinical Trials; Combined Modality Therapy; Complex; DNA Sequence Alteration; Data; Data Set; Disease; Dissection; Early Diagnosis; Engineering; Evaluation; FOLH1 gene; Failure; Fibroblasts; Genetic Transcription; Genomics; Goals; Heterogeneity; Image; Immune; In complete remission; Incidence; Invaded; Lesion; Lymphatic; Lymphovascular; MRI Scans; Macrophage; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Metabolism; Metastatic/Recurrent; Modeling; Molds; Molecular; Molecular Analysis; Multifocal Lesion; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Newly Diagnosed; Operative Surgical Procedures; Outcome; PTEN gene; Pathologic; Patients; Permeability; Phenotype; Population; Positron-Emission Tomography; Pre-Clinical Model; Prostate; Prostatectomy; Prostatic Neoplasms; Randomized; Receptor Signaling; Resistance; Sampling; Scanning; Slice; Specimen; Stromal Cells; TP53 gene; Technology; Testing; Tumor Cell Invasion; Universities; Wisconsin; Work; abiraterone; advanced prostate cancer; arm; biomarker development; cell type; cohort; digital; docetaxel; drug development; exome sequencing; high risk; hormone therapy; immune cell infiltrate; inhibitor; lymphatic Invasion; lymphatic vessel; men; microphysiology system; migration; molecular phenotype; neoplastic cell; novel; novel therapeutic intervention; patient population; phase II trial; phase III trial; potential biomarker; prospective; prostate cancer cell; prostate cancer metastasis; prostate cancer risk; radiological imaging; response; success; technology platform; therapeutic target; therapy resistant; tool; transcriptome sequencing; transcriptomics; tumor; tumor DNA; tumor growth; tumor microenvironment

PROJECT SUMMARY There is an increasing incidence of men with newly diagnosed prostate cancer (PC) presenting with locally advanced or metastatic disease, a population that comprises >60% of the men who die from the disease. The failure of early detection has led to the initiation of multiple clinical trials testing neoadjuvant therapies in an attempt to cure these patients. Analysis of pre-treatment samples from neoadjuvant trials have identified genomic alterations that associate with a treatment resistance. More recent studies indicate the tumor microenvironment (TME) can initiate the metastatic cascade. However, it remains unclear how and when genomic alterations co- opt different cell types in a complex 3-dimensional TME to initiate the metastatic cascade. We have recently found that activated fibroblasts and macrophage sub-populations induce lymphovascular sprouting and permeability. Based on these data sets, we hypothesize that somatic alterations in tumor DNA co-opt stromal and immune cells in the TME to promote invasion and intravasation of lympho-vascular channels. To test this hypothesis, we have three cohorts of patients with high-risk prostate cancer (surgery alone, neoadjuvant Abiraterone, and neoadjuvant chemohormonal therapy) that undergo PSMA PET/MRI scans prior to surgery. This scan is used to develop 3D mold of the prostate to perform whole mount sectioning and dissection of multi-focal PC for multi-plex molecular analysis. Samples from these specimens are used to create patient-specific “TMEs on a Chip” using a humanized Micro-Physiologic System (MPS) of the prostate with surrounding lympho-vasculature. This novel model system allows culture of patient tumor cells and stromal cells to identify the factors that induce lymphatic permeability and culminate in tumor invasion and intravasation. Success in these studies will identify the biologic interactions in the TME that can initiate the metastatic cascade as potential biomarkers and therapeutic targets for men with high-risk, locally advanced PC. In Aim 1 we will perform whole exome and transcriptome sequencing, across 3D whole mount sections identified by PSMA PET/MRI, in untreated patients to evaluate heterogeneity and determine the impact of neoadjuvant ARSIs and docetaxel across 3D multifocal PC. In Aim 2, we extend spatial mapping with PSMA PET/MRI and IHC data to perform transcriptional Digital Spatial Profiling (DSP) on whole-mount sections collected in Aim 1. This integration will test whether distinct CAF and immune cell infiltrates associate with genomic alterations in a spatial configuration of cells invading regional lymphovascular channels. In Aim 3, we use LumeNEXT MPS technology to create humanized lymphatic vessels cultured in patient-specific humanized prostate TMEs, with genomically engineered PC cells, that reflect the molecular and cellular signatures identified in Aims 1 and 2. When completed, the outcome of this work will advance the field by helping us to understand how prostate cancer metastasizes for both biomarker and drug development.

项目摘要 新诊断的前列腺癌（PC）男性的发病率越来越高， 晚期或转移性疾病，包括>60%死于该疾病的男性的人群。的 早期检测的失败导致了多项临床试验的启动，这些试验在一个 试图治愈这些病人。对新辅助治疗试验的治疗前样本进行分析， 与治疗抗性相关的改变。最近的研究表明肿瘤微环境 (TME)可以启动转移级联反应然而，目前尚不清楚基因组改变如何以及何时共同作用。 在复杂的三维TME中选择不同的细胞类型以启动转移级联。我们最近 发现活化的成纤维细胞和巨噬细胞亚群诱导淋巴管发芽， 磁导率基于这些数据集，我们假设肿瘤DNA的体细胞改变与肿瘤细胞的增殖有关。 TME中的基质细胞和免疫细胞促进淋巴血管的侵袭和内渗 渠道为了验证这一假设，我们有三组高危前列腺癌患者（手术 单独、新辅助阿比特龙和新辅助化学激素疗法）进行PSMA PET/MRI扫描 在手术前。该扫描用于开发前列腺的3D模型，以执行整体安装切片， 多焦点PC的解剖用于多重分子分析。从这些标本中提取的样本 使用前列腺的人源化微生理系统（MPS）的患者特异性“芯片上的TME”， 淋巴管周围这种新的模型系统允许培养患者肿瘤细胞和基质细胞 以确定诱导淋巴渗透性并最终导致肿瘤浸润和内渗的因素。 这些研究的成功将确定TME中可以启动转移级联反应的生物相互作用 作为潜在的生物标志物和治疗目标的男性高风险，局部晚期PC。在目标1中， 在通过PSMA鉴定的3D完整切片上进行全外显子组和转录组测序 PET/MRI，在未经治疗的患者中评价异质性并确定新辅助ARSI的影响， 多西他赛在3D多焦点PC中的应用。在目标2中，我们使用PSMA PET/MRI和IHC数据扩展了空间映射， 对Aim 1中收集的整体切片进行转录数字空间分析（DSP）。这 整合将测试不同的CAF和免疫细胞浸润是否与空间分布中的基因组改变相关。 细胞侵入局部淋巴血管通道的结构。在Aim 3中，我们使用LumeNext MPS技术 以产生在患者特异性人源化前列腺TME中培养的人源化淋巴管， 工程化的PC细胞，其反映了目的1和2中鉴定的分子和细胞特征。当 完成后，这项工作的结果将通过帮助我们了解前列腺癌如何 用于生物标志物和药物开发。