The stromal microenvironment as a co-organizer of bladder carcinogenesis and progression

基质微环境作为膀胱癌发生和进展的共同组织者

• 批准号: 10519080
• 负责人: Keith Syson Chan
• 金额: $ 174.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 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 2022-12-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10519080
• 关键词: Address; Affect; Antitumor Response; B-Lymphocytes; Basic Science; Benchmarking; Bioinformatics; Biological; Biological Markers; Biology; Bladder; Cancer Biology; Cancer Patient; Carcinogens; Cell Communication; Cells; Clinical; Coin; Communication; Communities; Data; Development; Diagnosis; Disease; Ensure; Fibroblasts; Fingerprint; Funding; Future; Genes; Genomics; Goals; Human; Immune; Immunoassay; Individual; Knowledge; Lesion; Lymphoid Tissue; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maps; Mediating; Medical center; Modeling; Multi-Institutional Clinical Trial; Muscle; Organ; Outcome; Paracrine Communication; Pathologic; Pattern; Persons; Pilot Projects; Population; Primary Lesion; Prognosis; Property; Proteins; Proteomics; Reporting; Research; Research Personnel; Resource Sharing; Role; Sampling; Side; T-Lymphocyte; Tumor-infiltrating immune cells; Urine; Urothelial Cell; Validation; War; Yin-Yang; anticancer research; base; biomarker development; biomarker validation; cancer type; candidate marker; carcinogenesis; cell type; clinical practice; cohort; driving force; fibroblast-activating factor; functional genomics; induced pluripotent stem cell; innovation; insight; knowledge integration; lymphotoxin beta receptor; mouse model; multidisciplinary; neoplastic cell; non-muscle invasive bladder cancer; novel; personalized intervention; progenitor; programs; prospective; recombinase; recruit; risk stratification; single cell technology; success; tertiary lymphoid organ; transcriptomics; translational oncology; tumor; tumor growth; tumor progression; urinary; urologic

OVERALL PROJECT SUMMARY Bladder cancer (BC) is the second most common urologic malignancy affecting 573,278 people worldwide in 2020. Pathologically, BC is diagnosed as non-muscle-invasive (NMI) and muscle-invasive (MI) disease. Here we define early bladder lesions as NMIBC. Major clinical gaps in NMIBC include i) lack of mechanistic insights defining NMIBC progression, and ii) lack of platform for risk stratification of NMIBC that recur but never progress (“non-progressors”), from those that progresses into MIBC (“progressors”) and consequently demonstrate poor prognosis. The goal of our Center is to tackle this clinical issue by deciphering the underlying mechanisms restraining or promoting the progression of early lesions (Project 1 & 2), and to leverage this novel biology as candidate biomarkers to risk-stratify aggressive NMIBC (Project 3). This proposal seeks to shift the current research paradigm in the field of NMIBC, by proposing a conceptually innovative tug-of-war between a tumor- restraining (Project 1) and a tumor-promoting mechanism (Project 2) in determining the outcome of early bladder lesions/NMIBC in becoming “progressors” or “non-progressors” (Project 3). Clinically, why “non-progressors” often recur but seldom progress, and what are the driving forces advancing “progressors” into MIBC with poor survival remain fundamental questions in field. Our tug-of-war hypothesis with two opposing forces is conceptually different to most other studies, which primarily focus on one side of the coin. Further, the integration of knowledge from Project 1 and 2 as a unified spatial proteomics and transcriptomics map by the Shared Resource Core will reveal spatial and temporal relationships between distinct fibroblast populations with opposing functions, their physical interactions with tumor and immune cell clusters, as well as their relationship to the biomarkers from Project 3. Benchmark of success: The knowledge gained here will shift clinical practice paradigm, by informing future NIMBC management through 1) the development of novel urinary profiling strategies that could risk stratify aggressive NMIBC (Project 1-3); 2) the identification of targets for future precision intervention, either by enhancing/sustaining the tumor-restraining mechanisms (Project 1) and/or inhibiting the tumor-promoting mechanisms (Project 2). The overall success of our program is further ensured by an extraordinary multi-investigator team that integrates three “organ-specific” bladder cancer investigators within Cedars-Sinai Medical Center. All have active R01s and individual NCI-funding track record in performing basic science research, translational bladder cancer research, or leading multi-center clinical trials on the discovery and validation of biomarkers. Finally, they propose to collect valuable retrospective and prospective NMIBC cohorts, which are essential to address the clinical questions posed within this proposal and will become available to the research community as a shared resource to advance the field.

项目总体概要 膀胱癌 (BC) 是第二大常见泌尿系统恶性肿瘤，影响全球 573,278 人 2020.病理学上，BC被诊断为非肌肉侵袭性（NMI）和肌肉侵袭性（MI）疾病。这里 我们将早期膀胱病变定义为 NMIBC。 NMIBC 的主要临床差距包括 i) 缺乏机制见解 定义 NMIBC 进展，以及 ii) 缺乏对复发但从未进展的 NMIBC 进行风险分层的平台 （“非进步者”），来自那些进步到 MIBC 的人（“进步者”）并因此表现出较差的 预后。我们中心的目标是通过破译潜在机制来解决这一临床问题 抑制或促进早期病变的进展（项目 1 和 2），并利用这种新颖的生物学作为 对侵袭性 NMIBC 进行风险分层的候选生物标志物（项目 3）。该提案旨在改变目前的 NMIBC 领域的研究范式，提出了肿瘤- 抑制（项目 1）和肿瘤促进机制（项目 2）在确定早期膀胱的结果中 病变/NMIBC 成为“进展者”或“非进展者”（项目 3）。临床上，为什么“无进展者” 经常复发但很少进步，推动“进步者”进入贫困 MIBC 的驱动力是什么？ 生存仍然是该领域的基本问题。我们与两种相反力量的拔河假设是 在概念上与大多数其他研究不同，大多数其他研究主要关注硬币的一面。此外，整合 来自项目 1 和 2 的知识作为共享的统一空间蛋白质组学和转录组学图谱 资源核心将揭示不同成纤维细胞群之间的空间和时间关系 相反的功能、它们与肿瘤和免疫细胞簇的物理相互作用以及它们的关系 项目 3 中的生物标志物。成功的基准：此处获得的知识将改变临床实践 范式，通过以下方式为未来的 NIMBC 管理提供信息：1) 开发新型尿液分析 可能对激进的 NMIBC 进行分层风险的策略（项目 1-3）； 2）确定未来目标 精准干预，通过增强/维持肿瘤抑制机制（项目 1）和/或 抑制肿瘤促进机制（项目2）。进一步确保了我们计划的整体成功 由一个非凡的多研究人员团队整合了三名“器官特异性”膀胱癌研究人员 位于雪松西奈医疗中心内。所有人都有活跃的 R01 和个人 NCI 资助的表演记录 基础科学研究、转化膀胱癌研究或领先的多中心临床试验 生物标志物的发现和验证。最后，他们建议收集有价值的回顾性和前瞻性的 NMIBC 队列对于解决本提案中提出的临床问题至关重要，并将成为 作为共享资源提供给研究界以推进该领域的发展。