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.

总体项目摘要 膀胱癌（BC）是全世界573,278人的第二常见泌尿科恶性肿瘤 2020年。从病理上讲，卑诗省被诊断为非肌肉侵入（NMI）和肌肉侵入性（MI）疾病。这里 我们将早期膀胱病变定义为NMIBC。 NMIBC中的主要临床差距包括i）缺乏机械见解 定义NMIBC的进展，ii）缺乏反复出现但从未进步的NMIBC风险分层的平台 （“非宣传者”），从发展为MIBC的人（“进度者”），因此证明了贫穷 预后。我们中心的目的是通过破译基本机制来解决这一临床问题 限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 候选生物标志物以风险分层为积极的NMIBC（项目3）。该提议试图改变当前 在NMIBC领域的研究范式，提出肿瘤之间的概念创新的拔河 限制（项目1）和促进肿瘤的机制（项目2）在确定早期膀胱的结果中 病变/NMIBC成为“进步者”或“非培训者”（项目3）。在临床上，为什么“非探测器” 经常反复出现，但很少进步，而贫穷的驱动力将“进步者”推向MIBC 生存仍然是现场的基本问题。我们用两个相反力量的拔河假说是 从概念上讲，与大多数其他研究不同，这主要关注硬币的一侧。此外，集成 项目1和2的知识作为统一的空间蛋白质组学和转录组学映射。 资源核心将揭示不同的成纤维细胞种群之间的空间和临时关系 相反的功能，它们与肿瘤和免疫群簇的身体相互作用及其关系 对项目3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，通过通知未来的NIMBC管理通过1）开发新型的尿液分析 可能有可能将积极进取的NMIBC分层的策略（项目1-3）； 2）确定未来目标 精确干预，通过增强/维持肿瘤缠身机制（项目1）和/或 抑制肿瘤促进机制（项目2）。进一步确保我们计划的总体成功 由一支非凡的多侵袭者团队组成了三个“器官特异性”膀胱癌研究员 在Cedars-Sinai医疗中心。所有人都有活跃的R01和单独的NCI资助往绩记录 基础科学研究，翻译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潜在的 NMIBC队列，这对于解决本提案中假定的临床问题至关重要，并将成为 研究社区可作为共享资源来推进该领域。