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

整体项目总结 膀胱癌(BC)是第二种最常见的泌尿系恶性肿瘤，全世界有573,278人患有膀胱癌 2020年。病理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的主要临床缺陷包括：1)缺乏机械性洞察力 定义NMIBC的进展，以及ii)缺乏复发但从未进展的NMIBC风险分层的平台 (“非进步者”)，从那些进入多边投资委员会的人(“进步者”)，因此表现得很差 预后。我们中心的目标是通过破译潜在的机制来解决这个临床问题 抑制或促进早期病变的进展(项目1和2)，并利用这一新的生物学作为 对侵袭性NMIBC进行风险分层的候选生物标志物(项目3)。这项提议旨在改变目前的 NMIBC领域的研究范式，通过提出一种概念上的创新拉锯战，在肿瘤- 抑制(方案1)和肿瘤促进机制(方案2)在决定早期膀胱预后中的作用 成为“进步者”或“非进步者”的损害/NMIBC(项目3)。临床上，为什么“无进展者” 经常重蹈覆辙但很少进步，是什么驱动力推动“进步者”进入贫穷的MIBC？ 在战场上，生存仍然是根本问题。我们的两个对立力量的拔河假说是 在概念上不同于大多数其他研究，这些研究主要关注硬币的一面。此外，整合 来自项目1和项目2的知识作为统一的空间蛋白质组学和转录组学图谱由共享 资源核心将揭示不同成纤维细胞群体之间的空间和时间关系 对立功能、与肿瘤和免疫细胞团的物理相互作用以及它们之间的关系 到项目3中的生物标志物：成功的基准：在这里获得的知识将改变临床实践 范式，通过1)新的尿谱分析的发展为未来的NIMBC管理提供信息 可能使激进的NMIBC分层的战略(项目1-3)；2)确定未来的目标 精确干预，通过加强/维持肿瘤抑制机制(项目1)和/或 抑制肿瘤促进机制(项目2)。我们的项目的全面成功得到了进一步的保证 由一个非凡的多名研究人员组成的团队，该团队整合了三名针对特定器官的膀胱癌调查人员 在锡达斯-西奈医疗中心。所有人都有活动的R01和个人NCI-Funding在业绩方面的记录 基础科学研究、转化性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和展望 NMIBC队列，这对于解决这项提案中提出的临床问题至关重要，并将成为 作为推动该领域发展的共享资源，可供研究界使用。

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.