Project 1: Combinatorial Molecular Tumor Drivers in Basal and Supra- basal Urothelial Cells

项目1摘要 癌症的准确诊断和有效治疗所面临的关键挑战之一是其 异质性膀胱癌（BC）尤其如此，目前已知膀胱癌包括 主要组织学类型（移行细胞癌、鳞状细胞癌、腺癌和小细胞癌） 细胞癌），最普遍的移行细胞癌（低度恶性）中的主要表型变异 乳头状BC和高级别浸润性BC）和肌肉浸润性BC内的分子亚型（如 管腔亚型和基底亚型）。重要的是，不同的BC实体在生物学上似乎是相当不同的。 行为、临床结果和对治疗的反应。然而，BC背后的确切机制 异质性仍然知之甚少，因此对快速和有意义临床研究 基础科学发现的翻译。因此，本提案旨在解决这一问题 通过专门针对一组高度流行遗传和分子事件， 在人BC中转化为鼠尿道上皮的不同细胞群。特定目标1将询问关键突变 激活RTK-PI 3 K-RAS通路的事件，以及9 p21中肿瘤抑制因子的丢失 位点，在低度乳头状BC形成的背景下。目标2将剖析组合驱动程序 p53缺陷沿着改变的DNA修复基因/组蛋白修饰剂的影响， 高级别侵袭性BC及其亚型。实验方法将结合联合收割机， 转基因、敲入、敲除和复合小鼠的产生和深入表征。统称 拟议的研究应显着增强我们对遗传、分子和细胞基础的理解 BC异质性。这反过来又会导致新的生物标志物小组的发展， 可靠地对BC变异进行分层，更准确地预测其进展概率和对 化疗、放疗和免疫治疗。BC变体的真正遗传、分子和细胞鉴定 也应该有助于发现治疗干预的新靶点。

Project 1 Summary One of the key challenges confronting the accurate diagnosis and effective treatment of cancer is its heterogeneous nature. This is particularly true with bladder cancer (BC) which is now known to comprise principal histological types (transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma and small cell carcinoma), major phenotypic variants within the most prevalent transitional cell carcinoma (low-grade papillary BC and high-grade invasive BC) and molecular subtypes within the muscle-invasive BC (such as luminal-subtype and basal-subtype). Importantly, different BC entities appear to be quite divergent in biological behavior, clinical outcome and response to therapies. However, the exact mechanism(s) underlying BC heterogeneity remain poorly understood, thus presenting a major hindrance for rapid and meaningful clinical translation of the basic science discoveries. The present proposal is therefore designed to address this important and pressing problem by specifically targeting a set of genetic and molecular events highly prevalent in human BC into different cell populations of murine urothelia. Specific Aim 1 will interrogate key mutational events that activate the RTK-PI3K-RAS pathway, in conjunction with the loss of tumor suppressors in the 9p21 locus, in the context of the formation of low-grade papillary BC. Aim 2 will dissect the combinatorial driver effects of p53 deficiency along with altered DNA repair genes/histone modifiers, in the context of the formation of high-grade invasive BC and potentially its subtypes. The experimental approaches will combine the generation and in-depth characterization of transgenic, knockin, knockout and compound mice. Together, the proposed studies should significantly enhance our understanding of the genetic, molecular and cellular bases of BC heterogeneity. This should in turn lead to the development of new biomarker panels that can more reliably stratify BC variants, more accurately predict their probability of progression and likelihood to respond to chemo-, radio- and immuno-therapeutics. The true genetic, molecular and cellular identification of BC variants should also help uncover new targets for therapeutic intervention.