Investigating mechanisms of bladder cancer metastasis

膀胱癌死亡的主要原因是由于转移，迄今为止转移性膀胱癌 （mMIBC）尚未得到广泛研究，许多突出问题仍未得到解决。的一个主要 阻碍mMIBC研究进展的挑战是缺乏合适的模型进行调查 体内转移进展。我们现在已经产生了新的基因工程小鼠模型（GEMM） 开发高渗透性的mMIBC。这些新的是基于我们建立的GEMM，其中膀胱特定 Pten和p53肿瘤抑制因子的共失活导致侵袭性疾病， 转移将这些Pten; p53小鼠与携带Arid 1a（一种表观遗传调节因子）功能缺失的小鼠杂交 在高比例的人类膀胱癌中失调，导致致死性膀胱癌， 转移发生率。此外，用低剂量的致癌物N-丁基-N，N-二甲基-N， N-（4-羟丁基）-亚硝胺（BBN）导致mMIBC，发生率>60%。与此同时，我们实施了 国家的最先进的系统生物学方法，以确定机械决定因素-主调节器（MR）-的 GEMM中的转移性进展。在GEMM中转移性肿瘤中富集的MR是保守的， 人膀胱癌，并富集与谱系可塑性相关的那些。识别靶向药物 这些保守的MR，我们实现了OncoTreat，这是一种计算算法， 为了验证这些药物，我们已经生成了一个 人类患者来源的类器官模型的广泛生物库。利用这些GEMM， 类器官和系统的方法，我们是理想的准备调查的假设，从过渡到 从侵袭前到转移性疾病是由主调节因子的顺序活动驱动的，包括谱系调节因子。 可塑性，这可以通过研究这些GEMM中的转移进展来阐明和靶向。我们将 追求三个具体目标：在目标1中，我们将利用mMIBC的GEMM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 阐明转移进展的主要调节因子，重点关注与从癌前病变向癌后病变转变相关的调节因子。 转移到转移性MIBC，和/或区分肿瘤与其相应转移，转移 不同的器官部位，以及，如果可行，来自明显转移的转移前簇。我们将优先考虑MR 与人类膀胱癌以及与谱系可塑性相关的保守基因。在目标3中， 将寻求使用OncoTreat算法识别用于mMIBC的新药，以识别逆转mMIBC的化合物。 转移的MR活性。我们将优先考虑候选药物，（1）靶向谱系可塑性机制， 和/或（2）对于不具有明显的可操作驱动突变的患者推断。总之，我们的研究 将提供mMIBC的生物学，机制和治疗的全面分析， 翻译目标是确定可能改善患者结局的新治疗靶点。

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.