Radiation modulation of cell plasticity programs determine prostate cancer oligometastatic potential

前列腺癌（PCa）的疾病失败模式表明，了解转移将导致最大的 治疗收益，并允许更合理的临床管理。整合所有网站的重要性 肉眼可见的疾病，包括原发性，以阻止进一步的转移性传播是由有限的支持， 前瞻性随机研究。然而，问题是，是否通过处理 在PCa中放射治疗的转移进一步阻碍了转移过程，并且存活率是未知的。是 通常认为转移是循环肿瘤细胞（CTC）离开原发灶的单向流动， 肿瘤和种植转移在一个遥远的网站，每个转移生长独立于其他。 然而，CTC可以经历周期性的“自接种”过程，其中具有转移潜能的细胞返回到正常细胞。 原发性肿瘤的“理想化”微环境和其他宏观肿瘤沉积物导致更多的 稳健的CTC。上皮-间充质可塑性（EMP）程序由上皮-间充质 间充质-上皮转化（EMT）和间充质-上皮转化（MET）是发育程序， 产生具有转移特性的上皮细胞。我们建议动态EMP程序指导PCa细胞 从EMT-MET来回恢复以便于自我播种。立体定向消融放射（SABR）是一种 高度聚焦，高剂量短辐射过程，适用于治疗转移，因为它靶向 癌细胞和肿瘤微环境（TME）细胞。有效针对TME的干预措施 SABR等成分似乎准备阻止转移瘤的自我播种和随后的成熟。 我们正处于启动我们的TERPS试验的最后阶段-2期随机转移性完全根除 原发性少转移性前列腺癌中前列腺确定性放疗后的病变。因此我们 已经提出了以下假设：（1）EMP程序控制自我播种和转移 （2）具有低EMT和/或高MET标志物的CTC代表了患有前列腺癌的男性， （3）转移灶的巩固性SABR改变了少转移性PCa的自然病程; （4）巩固性SABR改变了未来转移成熟的可能性，这可以通过以下方法检测到： CTC标志物谱和计数水平和/或组织、液体或成像生物标志物的变化。我们将 测试以下两个目标。目的#1：循环肿瘤细胞（CTC）的上皮-间质可塑性 用SABR治疗的患有寡转移性前列腺癌的男性的生物标志物。我们将采取一些措施， 从我们的TERPS试验中进行相关的组织、液体、成像和免疫研究，以检查EMP标志物- EMT和MET。目的#2：确定SABR对上皮细胞中前列腺癌自种植的影响。 间质可塑性前列腺癌小鼠模型。使用基于单元的EMP PCa模型和串行非 在小鼠中进行侵入性成像，以测试PCa的自我播种假设以及EMP因素是否调节自我播种。

Patterns of disease failure in prostate cancer (PCa) suggest understanding metastasis will result in the largest therapeutic gains and allow for more rationale clinical management. The importance of consolidating all sites of macroscopic disease including the primary to impede further metastatic dissemination is backed by limited prospective randomized studies. However, the question of whether total consolidation by treating the metastases with radiation in PCa further impedes the metastatic process and survival is unanswered. It is generally assumed that metastasis is a unidirectional flow of circulating tumor cells (CTCs) leaving the primary tumor and seeding a metastasis at a distant site with each metastasis growing independently of the others. However, CTCs may undergo a cyclical “self-seeding” process, wherein cells with metastatic potential return to the “idealized” microenvironment of the primary tumor and other macroscopic tumor deposits resulting in more robust CTCs. Epithelial-mesenchymal plasticity (EMP) programs composed of the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are developmental programs that can engender epithelial cells with metastatic properties. We propose the dynamic EMP program directs PCa cells to revert back and forth from EMT-MET to facilitate self-seeding. Stereotactic ablative radiation (SABR) is a highly focused, high-dose short radiation course that is suited for treatment of metastases as it targets the cancer cells and tumor microenvironment (TME) cells. Interventions that effectively target the TME component, such as SABR, appear poised to arrest self-seeding and subsequent maturation of metastases. We are in the final stages to launch our TERPS trial - Phase 2 randomized Total Eradication of metastatic lesions following definitive Radiation to the Prostate in de novo oligometaStatic prostate cancer. Thus, we have developed the following HYPOTHESES: (1) EMP programs control self-seeding and the metastatic potential of PCa; (2) CTCs with low EMT and/or high MET markers are representative of men with oligometastatic PCa; (3) Consolidative SABR of metastases alters the natural history of oligometastatic PCa; and, (4) Consolidative SABR alters the potential for maturation of future metastases that can be detected by changes in CTC marker profiles and enumeration levels and/or tissue, liquid or imaging biomarkers. We will test the following two aims. AIM #1: Epithelial-mesenchymal plasticity of circulating tumor cells (CTCs) are biomarkers for men with oligometastatic prostate cancer treated with SABR. We will pursue a number of correlative tissue, liquid, imaging and immune studies from our TERPS trial to examine for EMP markers - EMT and MET. AIM #2: To determine the effects of SABR on prostate cancer self-seeding in epithelial- mesenchymal plasticity prostate cancer mouse models. Use cell based EMP PCa models and serial non- invasive imaging in mice to test the self-seeding hypothesis for PCa and if EMP factors modulate self-seeding.