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 异质的自然。对于膀胱癌(BC)尤其如此，目前已知的膀胱癌包括 主要组织学类型(移行细胞癌、鳞癌、腺癌和小细胞癌 细胞癌)，最常见的移行细胞癌(低级别)中的主要表型变异 乳头型BC和高度侵袭性BC)和肌肉内侵袭性BC的分子亚型(如 管腔亚型和基底型)。重要的是，不同的BC实体在生物学上似乎有很大的差异 行为、临床结果和对治疗的反应。然而，BC背后的确切机制(S) 人们对异质性仍然知之甚少，因此对快速而有意义的临床研究构成了主要障碍。 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的遗传和分子事件来解决重要而紧迫的问题 在人BC中转化为不同细胞群的小鼠尿路感染。特定目标1将审问关键突变 激活RTK-PI3K-RAS通路的事件，与9p21中肿瘤抑制因子的丢失有关 点状，在低度乳头状BC形成。目标2将剖析组合驱动因素 P53缺失和DNA修复基因/组蛋白修饰物改变在形成过程中的作用 高级别侵袭性BC及其可能的亚型。实验方法将结合 转基因小鼠、基因敲除小鼠、基因敲除小鼠和复合小鼠的产生和深入鉴定。团结在一起， 拟议的研究将显著增强我们对遗传、分子和细胞基础的理解。 BC的异质性。这将反过来导致新的生物标志物小组的开发，这些小组可以 可靠地对BC变异体进行分层，更准确地预测其进展概率和对 化疗、放射和免疫疗法。BC变异体的真实遗传、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.