Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer

基质成纤维细胞在推动侵袭性前列腺癌和膀胱癌出现中的作用的空间和机制评估

• 批准号: 10831342
• 负责人: Keith Syson Chan
• 金额: $ 8.35万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10831342
• 关键词: Address; Automobile Driving; Award; Biological Process; Cancer Cell Growth; Cell Communication; Cell Compartmentation; Cells; Collaborations; Data; Development; Disease; Epithelial-Stromal Communication; Epithelium; Fibroblasts; Foundations; Future; Gene Expression; Genetic; Genetically Engineered Mouse; Genitourinary system; Genomics; Grant; Growth; Human; Immune; Immunohistochemistry; In Situ; In Situ Hybridization; Institution; Intercept; Invaded; Investigation; Knowledge; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Membrane Glycoproteins; Methods; Modeling; Molecular; Mutation; Nature; Neoplasm Metastasis; Paracrine Communication; Parents; Patient-Focused Outcomes; Phenotype; Pilot Projects; Population; Process; Public Health; Research; Role; Stromal Cells; Testing; Therapeutic; Tissues; Tumor Promotion; Urogenital Cancer; Validation; Work; angiogenesis; cancer cell; cancer invasiveness; cancer type; carcinogenicity; clinically relevant; fibroblast-activating factor; human tissue; improved; insight; inter-institutional; interest; molecular phenotype; muscle invasive bladder cancer; nano-string; novel; novel strategies; novel therapeutic intervention; overexpression; programs; response; risk stratification; spatial integration; spatial relationship; theranostics; therapeutic target; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Prostate and bladder cancers are the two most frequent genitourinary cancers, and their progression from low to high aggressiveness remains poorly understood. Stromal-epithelial-immune interactions, particularly involving fibroblast activation protein (FAP)-expressing fibroblasts, may contribute to tumor aggressiveness. However, the precise role of these cells in the tumor microenvironment (TME) and the molecular mechanisms driving cancer progression remain unclear. We hypothesize that FAP+ fibroblasts engage in cell-cell interactions and paracrine signaling, supporting cancer cell growth and invasion, leading to aggressive cancer formation. To test this hypothesis, we propose two specific aims: (1) Integrate spatial transcriptomics and multiplex immunohistochemistry/in situ hybridization (IHC/ISH) analyses of human prostate and bladder cancer tissues to define the molecular phenotype and spatial relationships between FAP+ fibroblasts, cancer cells, and other stromal cell compartments in the TME; and (2) Investigate the functional role of FAP+ fibroblasts in aggressive prostate and bladder cancer using genetically engineered mouse models (GEMMs) and spatial transcriptomic alterations with and without FAP genetic disruption. We will perform cutting-edge spatially resolved transcriptomic and multiplex IHC/ISH analysis of human prostate and bladder cancer tissues using advanced platforms. These data will be integrated using the AstroPath platform, which will be extended to handle the spatial transcriptomics data alongside the multiplex in situ methods. To investigate the functional role of FAP+ fibroblasts in aggressive cancer development, we will employ GEMMs and evaluate spatial transcriptomic alterations with and without FAP genetic disruption. These data will augment phenotypic studies and allow investigation of FAP's role in cell-cell spatial relationships and paracrine signaling mechanisms. Findings will be validated using multiplex IHC/ISH panels. Expected Results and Impact: Our study will provide insights into FAP's role in prostate and bladder cancer and its potential as a therapeutic and theranostic target. The use of spatial transcriptomics and multiplex in situ immunohistochemistry will enable identification of FAP-expressing cells and their spatial relationship with other TME components. The use of GEMMs will facilitate investigating FAP's functional role in tumor growth, angiogenesis, and metastasis. Validating findings in human tissues will provide clinical relevance. Overall, this study will contribute to understanding the molecular mechanisms underlying prostate and bladder cancer, potentially leading to novel therapeutic strategies targeting FAP. This pilot study will establish the feasibility of these methods and models in our groups, allowing comparison of FAP+ fibroblasts' role in both cancer types and laying the foundation for longitudinal collaboration beyond the Supplement award to facilitate inter-institutional collaboration through our U54 TBEL consortium.

抽象的 本申请是为了响应被识别为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 23-045。前列腺癌和膀胱癌是两种最常见的泌尿生殖系统癌症及其进展 从低到高的攻击性仍然知之甚少。基质-上皮-免疫相互作用，特别是 涉及表达成纤维细胞活化蛋白（FAP）的成纤维细胞，可能有助于肿瘤的侵袭性。 然而，这些细胞在肿瘤微环境（TME）中的精确作用及其分子机制 驱动癌症进展的因素仍不清楚。我们假设 FAP+ 成纤维细胞参与细胞间相互作用 和旁分泌信号，支持癌细胞生长和侵袭，导致侵袭性癌症形成。到 为了检验这一假设，我们提出了两个具体目标：（1）整合空间转录组学和多重分析 对人类前列腺癌和膀胱癌组织进行免疫组织化学/原位杂交 (IHC/ISH) 分析 定义 FAP+ 成纤维细胞、癌细胞和其他细胞之间的分子表型和空间关系 TME 中的基质细胞区室； (2) 研究 FAP+ 成纤维细胞在侵袭性 使用基因工程小鼠模型 (GEMM) 和空间转录组学研究前列腺癌和膀胱癌 有和没有 FAP 基因破坏的改变。我们将进行尖端的空间解析 使用先进技术对人类前列腺癌和膀胱癌组织进行转录组和多重 IHC/ISH 分析 平台。这些数据将使用 AstroPath 平台进行集成，该平台将被扩展以处理空间数据 转录组学数据以及多重原位方法。研究 FAP+ 成纤维细胞的功能作用 在侵袭性癌症发展中，我们将采用 GEMM 并评估空间转录组变化 并且没有 FAP 基因破坏。这些数据将增强表型研究并允许对 FAP 进行调查 在细胞间空间关系和旁分泌信号机制中的作用。调查结果将通过以下方式进行验证： 多重 IHC/ISH 面板。预期结果和影响：我们的研究将深入了解 FAP 在前列腺中的作用 膀胱癌及其作为治疗和治疗诊断目标的潜力。空间转录组学的应用 多重原位免疫组织化学将能够鉴定表达 FAP 的细胞及其空间 与其他 TME 组件的关系。 GEMM 的使用将有助于调查 FAP 在以下方面的功能作用： 肿瘤生长、血管生成和转移。在人体组织中验证研究结果将提供临床意义。 总的来说，这项研究将有助于了解前列腺和膀胱的分子机制 癌症，可能导致针对 FAP 的新治疗策略。这项试点研究将建立 这些方法和模型在我们组中的可行性，可以比较 FAP+ 成纤维细胞在两者中的作用 癌症类型，并为补充奖之外的纵向合作奠定基础，以促进 通过我们的 U54 TBEL 联盟进行机构间合作。