Determine the Microphthalmia Transcription Factor (MITF)-regulated cell rewiring mechanisms in lethal prostate cancer

一旦前列腺癌发展到晚期去势抵抗阶段，它就变成了一个无法治愈的致命疾病 疾病。到目前为止，对肿瘤细胞的内在生物学过程的了解涉及到肿瘤的病理生物学 致命性前列腺癌仍然是有限的。我们的研究计划旨在阐明可操作的分子 利用具有临床意义的人前列腺癌维持致命性肿瘤侵袭性的机制 癌症模型。我们实验室和其他实验室的研究表明，主要的调节转录因子 通过调节Key的表达来调节可操作的机制，从而动态地对癌细胞进行重新编程 前列腺癌的核生长因子受体，如雄激素受体。通过全面的 包括原发组织和转移组织的人类转录型前列腺癌公共数据库的分析 样本，再加上体外和体内患者衍生的实验模型，我们已经确定 与致命性前列腺癌的病理生物学相关的转录调控机制。最相关的 对于这一建议，我们的研究指出了小眼炎转录因子(MITF)在晚期 致命的前列腺癌。低MITF水平与原发性前列腺癌和疾病复发有关 前列腺癌患者。值得注意的是，功能研究表明，在前列腺癌中，MITF调节生长 并通过控制一个独特的临床相关基因网络来抵抗雄激素剥夺治疗。 事实上，计算研究表明，MITF调节特定关键癌蛋白的蛋白质合成 和前列腺特异性生长因子，如MYC和AR。因此，根据这些结果，我们假设 MITF通过调节转录和翻译参与致命性前列腺癌的发病 将癌细胞重新编程为耐药致命状态的机制。我们将对此进行调查 假设如下：在目标1中，我们将探索MITF调控的转录机制与以下相关 致命性前列腺癌，重点是不同的MITF亚型，以描述它们的个体功能以及 确定临床相关的MITF调节的下游效应基因。在目标2中，我们将研究MITF如何 调节蛋白质的合成，集中于特定的翻译起始亚单位以确定它们在 调节特定mRNAs的翻译，以及MITF和MYC之间的调节串扰。最后，在 目的3我们将研究致死性前列腺癌循环肿瘤细胞中这些发现的临床相关性。 患者以及在临床前模型中测试靶向蛋白质合成和 雄激素剥夺疗法作为延缓去势发展的综合治疗策略 低MITF前列腺癌的耐药性。归根结底，这些研究将拓宽我们对 主控转录因子如何管理复杂的信号网络，从而重新连接癌症 细胞，在这种情况下，通过调节翻译，这可能提供新的药物治疗机会 前列腺癌患者。

Once prostate cancer progresses to an advanced castration resistant stage it becomes an incurable deadly disease. To date the understanding of the intrinsic tumor cell biology processes involved in the pathobiology of lethal prostate cancer remains limited. Our research proposal aims to elucidate actionable molecular mechanisms that sustain the aggressiveness of lethal tumors by using clinically significant human prostate cancer models. Work from our laboratory and others have revealed that master regulator transcription factors regulate actionable mechanisms that dynamically reprogram the cancer cell by regulating the expression of key nuclear growth factor receptors of prostate cancer such as the Androgen receptor. Through the comprehensive analysis of human transcriptomic prostate cancer public databases that include primary and metastatic tissue samples, coupled with in vitro and in vivo patient derived experimental models, we have identified transcriptionally regulating mechanisms associated with the pathobiology of lethal prostate cancer. Most relevant to this proposal, our studies point to a key role of the Microphthalmia Transcription Factor (MITF) in advanced lethal prostate cancer. Low MITF levels are associated with lethal prostate cancer and disease relapse in primary prostate cancer patients. Notably, functional studies suggest that in prostate cancer MITF regulates the growth and confers resistance to androgen deprivation therapy by controlling a distinct clinically relevant gene network. Indeed, computational studies suggest that MITF regulates the protein synthesis of specific key oncoproteins and prostate specific growth factors, such as MYC and AR. Thus, based on these results, we hypothesize that MITF contributes to the pathogenesis of lethal prostate cancer by regulating both transcriptional and translational mechanisms that reprogram the cancer cell into a therapy resistant lethal state. We will investigate this hypothesis as follows: In aim 1 we will explore the MITF regulated transcriptional mechanisms associated with lethal prostate cancer, focusing on distinct MITF isoforms to delineate their individual functions, as well as determine the clinically relevant MITF regulated downstream effector genes. In aim 2 we will examine how MITF regulates protein synthesis, focusing on specific translation initiation subunits to determine their function in regulating the translation of specific mRNAs, as well as regulatory crosstalk between MITF and MYC. Finally, in aim 3 we will study the clinical relevance of these findings in circulating tumor cells from lethal prostate cancer patients along with testing the in vivo efficacy in preclinical models of targeting protein synthesis together with androgen deprivation therapy as a combined therapeutic strategy to delay the development of castration resistance in low MITF prostate tumors. Ultimately, these studies are poised to broaden our understanding of how master regulator transcription factors govern an intricate complex signaling network that rewires the cancer cell, in this case through regulation of translation, which may offer novel druggable therapeutic opportunities for prostate cancer patients.