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

Nanog 的上调作为癌症耐药性的创新机制。

• 批准号: 8827727
• 负责人: TZYY-CHOOU WU
• 金额: $ 17.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827727
• 关键词: Antineoplastic Agents; Apoptosis; Cancer Biology; Cancer Intervention; Cancer Model; Cancer Patient; Cancer Relapse; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Development; Disease; Disease Management; Drug resistance; Ectopic Expression; Event; Evolution; Face; Generations; Genes; Genetic Transcription; Health; Homeobox; Human; Immune; Immunologic Surveillance; Knowledge; Lead; Light; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Measures; Mediating; Modeling; Molecular; Mus; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pluripotent Stem Cells; Primary Neoplasm; Process; Public Health; Recurrence; Recurrent disease; Reporting; Resistance; Role; SCID Mice; SKOV3 cells; Signal Transduction; Small Interfering RNA; Staining method; Stains; Stem cells; Transcriptional Activation; Tumor Tissue; Up-Regulation; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; driving force; improved; innovation; insight; mortality; nanoparticle; neoplastic cell; novel; novel strategies; outcome forecast; pressure; programs; response; self-renewal; stem; stemness; success; therapy resistant; transcription factor; tumor; tumor progression

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.

描述（由申请人提供）：癌症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卫生负担，有必要了解这种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，肿瘤细胞经历了获得Nanog的进化，Nanog是一种对多能干细胞自我更新至关重要的同源盒转录因子。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。由于干细胞样状态允许细胞无限期的自我更新，并且由于 Akt 途径协调一系列促生存信号的激活，因此我们推断 Nanog 还赋予肿瘤细胞耐药性。我们假设 Nanog 的增加是肿瘤细胞适应宿主免疫防御和治疗的基础，因此可能代表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，当前项目的目的是研究 Nanog 在耐药性中的作用。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进化； (2)表征Nanog在赋予肿瘤细胞耐药性中的作用； (3) 表征 Nanog 介导肿瘤细胞耐药性的分子机制。由于多种原因，该项目的成功实施具有重要意义。首先，它揭示了 Nanog 作为肿瘤细胞干样状态和耐药性之间的分子联系。这一见解将直接导致癌症患者更成功地选择治疗和疾病管理。其次，通过确定 Nanog-Tcl1a-Akt 通路是免疫逃逸和耐药性的门户，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问题的原理。基于这些原因，我们相信这项研究将极大地提高我们对癌症生物学的了解，并对公共健康产生强大的影响。