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

一旦前列腺癌进展到晚期去势抵抗阶段，它就会成为无法治愈的致命疾病 疾病。迄今为止，人们对涉及肿瘤病理学的内在肿瘤细胞生物学过程的了解 致命的前列腺癌仍然有限。我们的研究计划旨在阐明可操作的分子 通过使用具有临床意义的人类前列腺来维持致命肿瘤的侵袭性的机制 癌症模型。我们实验室和其他实验室的工作表明，主调节转录因子 通过调节关键的表达来调节可操作的机制，动态地重新编程癌细胞 前列腺癌的核生长因子受体，例如雄激素受体。通过综合 对包括原发组织和转移组织的人类转录组前列腺癌公共数据库进行分析 样本，加上体外和体内患者衍生的实验模型，我们已经确定 与致命性前列腺癌病理学相关的转录调节机制。最相关的 针对这一提议，我们的研究指出了小眼转录因子 (MITF) 在高级疾病中的关键作用 致命的前列腺癌。低 MITF 水平与致命性前列腺癌和原发性前列腺癌疾病复发有关 前列腺癌患者。值得注意的是，功能研究表明，MITF 在前列腺癌中调节生长 并通过控制独特的临床相关基因网络赋予对雄激素剥夺疗法的抵抗力。 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 以及前列腺特异性生长因子，例如 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促进致命性前列腺癌的发病机制 将癌细胞重新编程为治疗抵抗性致死状态的机制。我们将对此进行调查 假设如下：在目标 1 中，我们将探索 MITF 调节的转录机制 致命的前列腺癌，重点关注不同的 MITF 同工型来描述其各自的功能，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 调节蛋白质合成，重点关注特定的翻译起始亚基以确定其功能 调节特定 mRNA 的翻译，以及 MITF 和 MYC 之间的调节串扰。最后，在 目标 3 我们将研究这些发现在致命性前列腺癌循环肿瘤细胞中的临床相关性 患者以及在靶向蛋白质合成的临床前模型中测试体内功效 雄激素剥夺疗法作为延缓去势发展的综合治疗策略 低 MITF 前列腺肿瘤的耐药性。最终，这些研究将拓宽我们对 主调节转录因子如何控制错综复杂的信号网络，从而重新连接癌症 细胞，在这种情况下通过翻译调节，这可能为以下疾病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.