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 该申请是为了响应特殊利益通知（NOSI）而提交 23-045。前列腺和膀胱癌是两个最常见的泌尿生殖器癌，它们的进展 从低到高侵略性仍然知之甚少。尤其是基质上皮 - 免疫相互作用 涉及表达成纤维细胞的成纤维细胞激活蛋白（FAP）可能有助于肿瘤侵袭性。 但是，这些细胞在肿瘤微环境（TME）和分子机制中的精确作用 驱动癌症进展尚不清楚。我们假设FAP+成纤维细胞参与细胞细胞相互作用 和旁分泌信号传导，支持癌细胞的生长和侵袭，导致侵袭性癌症形成。到 检验该假设，我们提出了两个具体目的：（1）整合空间转录组学和多重目标 免疫组织化学/原位杂交（IHC/ISH）分析人类前列腺和膀胱癌组织 定义FAP+成纤维细胞，癌细胞和其他的分子表型和空间关系 TME中的基质细胞室； （2）研究FAP+成纤维细胞在侵略性中的功能作用 使用基因工程的小鼠模型（GEMM）和空间转录组，前列腺和膀胱癌 有和没有FAP遗传破坏的变化。我们将执行最先进的空间解决 使用先进的人类前列腺和膀胱癌组织的转录组和多重IHC/ISH分析 平台。这些数据将使用Astropath平台集成，该平台将扩展以处理空间 转录组学数据与多重原位方法一起。研究FAP+成纤维细胞的功能作用 在激进的癌症发展中，我们将采用GEMMS并评估空间转录组的改变 并且没有FAP遗传破坏。这些数据将增加表型研究，并允许研究FAP 在细胞细胞空间关系和旁分泌信号传导机制中的作用。调查结果将使用 多重IHC/ISH面板。预期结果和影响：我们的研究将为FAP在前列腺中的作用提供见解 和膀胱癌及其作为治疗和治疗靶标的潜力。空间转录组学的使用 多路复用原位免疫组织化学将使表达FAP的细胞及其空间鉴定 与其他TME组件的关系。 GEMM的使用将有助于调查FAP在 肿瘤生长，血管生成和转移。验证人体组织中的发现将提供临床相关性。 总体而言，这项研究将有助于理解前列腺和膀胱的分子机制 癌症，可能导致针对FAP的新型治疗策略。这项试验研究将确定 这些方法和模型在我们的小组中的可行性，从而可以比较FAP+成纤维细胞在这两个中的作用 癌症类型并为纵向合作的基础奠定了补充奖的纵向合作奖 通过我们的U54 TBEL财团进行的机构间合作。