Investigating mechanisms of bladder cancer metastasis

膀胱癌死亡的主要原因是转移，但到目前为止转移性膀胱癌。 (MMIBC)尚未得到广泛研究，许多突出问题仍未解决。其中一个主要的 阻碍mMIBC研究进展的挑战是缺乏合适的模型来进行研究 体内转移性进展。我们现在已经产生了新的基因工程小鼠模型(GEMM) 形成具有高度渗透性的mMIBC。这些新的是基于我们建立的GEMM，其中特定于膀胱 Pten和P53抑癌基因的共同失活导致侵袭性疾病，其发病率较低 转移。将Pten；p53小鼠与表观遗传调节因子ARID1A功能丧失的小鼠杂交 这在很高比例的人类膀胱癌中是失调的，导致80%的致命膀胱癌。 转移的发生率。此外，用低剂量的致癌物N-丁基-Pten；p53治疗Pten；P53小鼠。 N-(4-羟基丁基)-亚硝胺(BBN)导致mMIBC，发病率为60%。同时，我们还实施了 最新的系统生物学方法识别机械决定因素--主调节因子(MRS)-- GEM的转移性进展。GEMM中富含转移瘤的MRS与 人类膀胱癌，富含那些与谱系可塑性相关的基因。以确定靶向药物 这些保守的MRS，我们实现了OncoTreat，一种基于以下因素对药物进行优先排序的计算算法 他们逆转生物相关先生活动的能力为了验证这些药物，我们已经产生了 广泛的人类患者生物库派生的器官模型。利用这些GEMM，人类患者衍生出 有机化合物和系统方法，我们理想地准备研究这样的假设：从 侵袭前期到转移性疾病是由主控调节因子的顺序活动驱动的，包括谱系 可塑性，这可以通过研究这些GEMM中的转移过程来阐明和靶向。我们会 追求三个具体目标：在目标1中，我们将利用mMIBC的GEM来系统地调查 体内转移进展的生物学过程和分子机制。在目标2中，我们将 阐明转移进展的主要调控因素，重点是那些与前 转移到转移的MIBC，和/或将肿瘤与其相应的转移、转移区分开来 转移到不同的器官部位，并在可行的情况下，从公开转移的转移前集群。我们将优先选择MRS。 与人类膀胱癌以及与谱系可塑性相关的基因保守的基因。在目标3中，我们 将寻求使用OncoTreat算法识别mMIBC的新药，以识别逆转 转移瘤的MRS活性。我们将优先考虑以下候选药物：(1)针对谱系可塑性机制， 和/或(2)被推断为没有明显的可操作的驱动程序突变的患者。总而言之，我们的研究 将提供对mMIBC的生物学、机制和治疗的全面分析，以及 确定可能改善患者预后的新的治疗靶点的翻译目标。

The major cause of bladder cancer deaths is due to metastasis, yet to date metastatic bladder cancer (mMIBC) has not been extensively studied and many salient issues remain unresolved. One of the major challenges that has hampered progress in studying mMIBC is the lack of suitable models to investigate metastatic progression in vivo. We have now generated novel genetically-engineered mouse models (GEMMs) that develop highly penetrant mMIBC. These new are based on our established GEMM, in which bladder-specific co-inactivation of the Pten and p53 tumor suppressors leads to invasive disease with a low incidence of metastasis. Crossing these Pten; p53 mice with mice harboring loss-of-function of Arid1a, an epigenetic regulator that is dysregulated in a high percentage of human bladder cancers, results in lethal bladder cancer with >80% incidence of metastasis. In addition, treatment of the Pten; p53 mice with a low dose of the carcinogen N-butyl- N-(4-hydroxybutyl)-nitrosamine (BBN) leads to mMIBC with >60% incidence. In parallel, we have implemented state-of-the-art systems biology approaches to identify mechanistic determinants—master regulators (MRs)—of metastatic progression in the GEMMs. MRs enriched in metastatic tumors in the GEMMs are conserved with human bladder cancer, and are enriched for those associated with lineage plasticity. To identify drugs that target these conserved MRs, we implemented OncoTreat, a computational algorithm that prioritizes drugs based on their ability to invert the activities of biologically-relevant MR. To validate these drugs, we have generated an extensive biobank of human patient derived organoid models. Leveraging these GEMMs, human patient derived organoids and systems approaches, we are ideally poised to investigate the hypothesis that the transition from pre-invasive to metastatic disease is driven by the sequential activities of master regulators, including for lineage plasticity, which can be elucidated and targeted by studying metastatic progression in these GEMMs. We will pursue three Specific Aims: In Aim 1, we will leverage our GEMMs of mMIBC to systematically investigate the biological processes and molecular mechanisms underlying metastatic progression in vivo. In Aim 2, we will elucidate master regulators of metastatic progression, focusing on those associated with the transition from pre- metastatic to metastatic MIBC, and/or that distinguish tumors from their corresponding metastases, metastases to different organ sites, and, as feasible, pre-metastatic clusters from overt metastases. We will prioritize MRs that are conserved with human bladder cancer, as well as those associated with lineage plasticity. In Aim 3, we will seek to identify new drugs for mMIBC using the OncoTreat algorithm to identify compounds that invert the activity of MRs of metastasis. We will prioritize candidate drugs that (1) target lineage plasticity mechanisms, and/or (2) are inferred for patients that do not have evident actionable driver mutations. Altogether, our studies will provide a comprehensive analysis of the biology, mechanisms, and treatments for mMIBC, with the translational goal of identifying new therapeutic targets that may improve patient outcomes.