Mechanisms regulating the formation of a pro-metastatic niche and tumor cell dormancy in the liver

摘要 胰腺导管腺癌(PDAC)是美国癌症相关死亡的第三大原因。 各州。对于pdac患者，转移是死亡的主要原因，肝脏是最常见的部位。 转移的可能性。因此，能够破坏转移过程的治疗方法代表着一个明显的未得到满足的需求。 实验室最近的工作表明，血清淀粉样蛋白A1/2蛋白(SAA)在癌症发展过程中释放 为肝脏的转移做好准备。在这个过程中，肝脏中形成了一个支持肿瘤转移的“生态位”。 播散性肿瘤细胞(DTC)的种植和定植。值得注意的是，SAA是肝脏的已知决定因素 通过天然免疫细胞表达的Toll样受体(TLRs)发挥作用的生物学。SAA也被证明是 协调急性期炎症反应，促进组织修复。然而，这些机制通过 其中SAA指导肝脏形成一个有利于转移的生态位，以及这个生态位对人肝细胞癌命运的影响 种植于肝脏的DTC仍不明确。因此，对这一生物学的理解具有很强的潜在信息 旨在阻止转移级联反应的新策略的开发。初步数据显示表达 正常肝脏巨噬细胞表面SAA受体的表达及TLR2和TLR4的体外诱导 SAA发出的信号，以及TLR2和TLR4在生态位内巨噬细胞上的表达增加。这些数据 提示TLR信号是促进转移的生态位的关键决定因素。初步数据还显示，在 当缺乏促进转移的生态位时，与肝脏相遇的DTCs进入休眠状态。这一发现表明 需要次级信号来“唤醒”处于休眠状态的癌细胞，并引发转移性生长。一致 因此，最近的研究表明，迁移的髓系细胞在逆转肿瘤细胞休眠中起到了作用。 阿龙。同样，我的初步数据显示，炎性单核细胞在形成的壁龛内积累 在肝脏里。因此，这一提议的中心假设是肝细胞释放的SAA激活了 驻留的肝巨噬细胞通过TLR信号指导转移前生态位的形成和 最终决定DCs在肝脏中的命运(即休眠与生长)。在目标一中，我将决定 SAA引导转移前生态位形成的机制。在目标二中，我将阐明 转移灶对DTC在肝脏中命运的影响。总而言之，这项建议的研究将推动我们的 对转移过程的理解，有可能找到新的治疗方法 干预癌症转移。此外，该项目将由一位著名的导师赞助， 在免疫学和癌症生物学方面的专业知识。这种赞助包括对导师和意志的承诺 发生在癌症免疫学和癌症生物学最重要的机构之一。这个项目还 包括研究生培训计划，该计划补充了科学研究的培训，并包括教学论 在癌症生物学和免疫学以及科学交流和教学方面的培训。

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related deaths in the United States. For patients with PDAC, metastasis is the major cause of mortality and the liver is the most common site of metastasis. Thus, therapies capable of disrupting the metastatic process represent a clear unmet need. Recent work in the lab showed that Serum Amyloid A1/2 proteins (SAA) released during cancer development precondition the liver for metastasis. In this process, a “pro-metastatic niche” forms in the liver that supports the seeding and colonization of disseminated tumor cells (DTCs). Notably, SAA is a known determinant of liver biology acting via toll-like receptors (TLRs) expressed by innate immune cells. SAA has also been shown to orchestrate an acute phase inflammatory response and to promote tissue repair. However, the mechanisms by which SAA directs formation of a pro-metastatic niche in the liver, and the impact of this niche on the fate of DTCs seeding the liver, remain ill-defined. Thus, an understanding of this biology has strong potential to inform the development of novel strategies aimed at derailing the metastatic cascade. Preliminary data show expression of SAA receptors on macrophages isolated from normal livers, in vitro induction of TLR2 and TLR4 reporter signals by SAA, and increased expression of TLR2 and TLR4 on macrophages within the niche. These data suggest that TLR signaling is a key determinant of the pro-metastatic niche. Preliminary data also show that, in the absence of a pro-metastatic niche, DTCs encountering the liver enter a dormant state. This finding suggests the need for a secondary cue to “awaken” dormant cancer cells and to trigger metastatic outgrowth. Consistent with this, recent studies have shown a role for migratory myeloid cells in reversing tumor cell dormancy in the lung. Similarly, my preliminary data show an accumulation of inflammatory monocytes within the niche that forms in the liver. Thus, the central hypothesis of this proposal is that SAA released by hepatocytes activates resident liver macrophages via TLR signaling to direct the formation of a pro-metastatic niche and ultimately direct the fate (i.e. dormancy versus outgrowth) of DTCs in the liver. In Aim one, I will determine the mechanisms by which SAA directs formation of the pro-metastatic niche. In Aim two, I will elucidate the impact of the pro-metastatic niche on DTC fate in the liver. Altogether, studies in this proposal will advance our understanding of the metastatic process with the potential to identify novel therapeutic approaches for intervening on cancer metastasis. In addition, this project will be sponsored by an established mentor with expertise in immunology and cancer biology. This sponsorship involves a commitment to mentorship and will occur at one of the foremost institutions in cancer immunology and cancer biology. This project also encompasses a graduate training plan which complements training in scientific research and includes didactics in cancer biology and immunology as well as training in scientific communication and teaching.