Upregulation of Nanog as an Innovative Mechanism for Cancer Drug Resistance.

描述(申请人提供)：癌症的进展和扩散是由于肿瘤细胞对内部免疫防御和外部治疗的适应。因此，为了减轻癌症造成的公共健康负担，有必要了解这一适应过程的分子基础。我们最近发现，在免疫和药物选择的过程中，肿瘤细胞都会朝着获得Nanog的方向进化，Nanog是一种同源盒转录因子，对多能干细胞的自我更新至关重要。我们报道肿瘤组织中Nanog的表达与临床预后相关。此外，我们发现Nanog将肿瘤细胞转化为干细胞样状态，并使它们能够通过Tcl1a-Akt途径逃避免疫控制。由于干细胞状态允许细胞无限自我更新，而且Akt通路协调一系列促生存信号的激活，我们推测Nanog也赋予肿瘤细胞耐药性。我们假设，Nanog的获得是肿瘤细胞适应宿主免疫防御和治疗的基础，因此可能是癌症进展的主要驱动力。由于我们已经确定了Nanog在免疫逃逸中的作用，本项目的目的是研究Nanog在耐药中的作用。我们的具体目标是：(1)表征肿瘤细胞在化疗药物选择下向Nanog表达和获得干细胞样表型的演化；(2)表征Nanog在肿瘤细胞耐药中的作用；(3)表征Nanog介导肿瘤细胞耐药的分子机制。由于以下几个原因，该项目的成功实施将具有重要意义。首先，它揭示了Nanog是肿瘤细胞中干细胞状态和耐药性之间的分子联系。这种洞察力将直接导致癌症患者更成功地选择治疗和管理疾病。其次，通过确定Nanog-Tcl1a-Akt通路是免疫逃逸和耐药的门户，这项研究揭示了癌症适应的过程。第三，该项目引入了一种新的癌症化疗方法。特别是，这项研究将证明干细胞转录网络可以合理靶向克服癌症耐药性问题的原理。基于这些原因，我们相信这项研究将极大地促进我们对癌症生物学的了解，并对公众健康产生强大的影响。

DESCRIPTION (provided by applicant): Cancer progression and dissemination is due to adaptation of tumor cells to internal immune defenses and to external therapy. Thus, to reduce the public health burden due to cancer, it is necessary to understand the molecular basis of this process of adaptation. We recently found that in the course of both immune and drug selection, tumor cells undergo evolution towards gain of Nanog, a homeobox transcription factor pivotal for the self-renewal of pluripotent stem cells. We reported that Nanog expression in tumor tissue correlates with clinical prognosis. Furthermore, we found that Nanog converts tumor cells into a stem-like state and enables them to escape immune control through the Tcl1a-Akt pathway. Since the stem-like state permits indefinite self-renewal of cells, and since the Akt pathway coordinates the activation of a host of pro-survival signals, we reason that Nanog also confers drug resistance to tumor cells. We hypothesize that gain of Nanog underlies adaptation of tumor cells to host immune defenses as well as to therapy, and thus may represent a major driving force for cancer progression. As we have already established the role of Nanog in immune escape, the purpose of the current project is to investigate the role of Nanog in drug resistance. Our specific aims are to: (1) characterize the evolution of tumor cells towards Nanog expression and gain of a stem-like phenotype under drug selection by chemotherapy; (2) characterize the role of Nanog in conferring drug resistance to tumor cells; and (3) characterize the molecular mechanisms through which Nanog mediates drug resistance in tumor cells. The successful implementation of this project will be significant for several reasons. First, it reveals Nanog as molecular link between the stem-like state and drug resistance in tumor cells. This insight would directly lead to more successful choice of therapy and management of disease in cancer patients. Second, by identifying the Nanog-Tcl1a-Akt pathway as a gateway to both immune escape and drug resistance, this study sheds light on the process of cancer adaptation. Third, this project introduces a new approach to cancer chemotherapy. In particular, this study will prove the principle that the transcription network of stem cells can be rationally targeted to overcome the problem of cancer drug resistance. Based on these reasons, we believe this study will greatly advance our knowledge of cancer biology and have strong public health impact.