A Novel Lineage Specific Metastasis Suppressor Pathway in Lung Cancer

肺癌中一种新的谱系特异性转移抑制途径

• 批准号: 8436668
• 负责人: Don X Nguyen
• 金额: $ 38.54万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-11 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436668
• 关键词: Accounting; Acute; Adenocarcinoma; Adenocarcinoma Cell; Adopted; Affect; Aggressive Clinical Course; Alveolar; Animals; Bioinformatics; Biological; Biological Process; Biology; Cancer Patient; Cell Fate Control; Cell Lineage; Cells; Cessation of life; Chest; Classification; Colorectal Cancer; Competence; Complex; Development; Diagnosis; Diagnostic; Disease; Distal; Distant; Epigenetic Process; Epithelial; Epithelial Cells; GATA6 transcription factor; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Homeostasis; Human; Immunocompetent; In Situ; Light; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant neoplasm of thorax; Metastatic Neoplasm to the Bone; Metastatic malignant neoplasm to brain; MicroRNAs; Modality; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Organ; Pathway interactions; Proteins; Recurrence; Repression; Risk; Role; Source; Specificity; Staging; Stem cells; System; Therapeutic; Tissue Microarray; Tissue Sample; Tissues; Xenograft Model; addiction; cancer cell; cell type; gain of function; in vivo; in vivo Model; innovation; insight; knockout gene; loss of function; malignant breast neoplasm; mortality; mouse model; novel; outcome forecast; progenitor; programs; research study; small hairpin RNA; stem; stem cell population; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Thoracic malignancies account for more deaths than prostate, breast and colorectal cancer combined. The most frequently diagnosed lung cancer subtypes is lung adenocarcinoma (ADC), which can metastasize rapidly to multiple vital organs. Despite recent advances in the genetic classification of lung cancers, the molecular and biological determinants of this aggressive clinical course remain unknown. The mammalian lungs are complex organs that require the specification of various epithelial cell types for proper homeostasis. By employing innovative computational and experimental approaches, we uncovered a unique link between differentiation specific gene expression patterns of certain lung epithelial cells and human ADC recurrences. In particular, we discovered a metastasis suppressor pathway associated with the cell fate transcription factors GATA6 and HOPX. We propose that these transcription factors cooperate to restrain multiple biological steps in the metastatic cascade. Moreover, we hypothesize that GATA6 and HOPX control a lineage-specific metastasis program that is selective for epithelial cells of the distal airways and the lug ADC subtype. To study this pathway, we will perform experiments that take advantage of spatio-temporally controlled gene gain or loss of function approaches in vivo. First, we will characterize the biological function(s) of GATA6 and HOPX during tumorigenesis, distant organ metastasis, and lung ADC differentiation using our established in vivo model of metastatic dissemination and colonization by human ADC cells. Second, we will develop a complementary model in genetically engineered mice, to study how loss of Gata6 and/or Hopx cooperates with Kras and p53 mutations at different stages of metastatic progression, and their associated effects on endogenous stem/progenitor cells of the murine airways. Finally, we will integrate multiple approaches to elucidate the downstream mechanism by which the GATA6/HOPX pathway restrains metastatic progression in human ADCs, through the control of their target gene, the Hsa-miR-302/367 cluster. Our project is predicted to reveal conserved epigenetic networks that control lung homeostasis, and how their perturbation endows thoracic cancers with metastatic competence to multiple tissues. The overall goal of our proposal may therefore shed new light into the origins of aggressive metastatic tumors, and provide insights into more accurate diagnostic modalities for lung cancer patients at risk for metastatic disease. PUBLIC HEALTH RELEVANCE: Thoracic malignancies are the principal source of cancer related deaths due to the rapid metastatic spread of lung cancer cells. Our novel multi-disciplinary approach proposes to reveal molecular programs that are specific to certain tissue cell types and which characterize this aggressive clinical course. We believe that this project wil reveal fundamental new principles in pulmonary biology as well as provide therapeutic insight for lung cancer patients at risk of metastatic disease.

描述（由申请人提供）：胸部恶性肿瘤造成的死亡人数比前列腺癌、乳腺癌和结直肠癌的总和还多。最常诊断的肺癌亚型是肺腺癌（ADC），它可以迅速转移到多个重要器官。尽管肺癌的遗传分类最近取得了进展，但这种侵袭性临床过程的分子和生物学决定因素仍然未知。哺乳动物的肺是复杂的器官，需要各种上皮细胞类型的规格才能正确发挥作用。 体内平衡。通过采用创新的计算和实验方法，我们发现了某些肺上皮细胞的分化特异性基因表达模式与人类 ADC 复发之间的独特联系。特别是，我们发现了与细胞命运转录因子 GATA6 和 HOPX 相关的转移抑制途径。我们提出这些转录因子协同抑制转移级联中的多个生物学步骤。此外，我们假设 GATA6 和 HOPX 控制谱系特异性转移程序，该程序对远端气道和 lug ADC 亚型的上皮细胞具有选择性。为了研究这一途径，我们将进行利用体内时空控制基因获得或功能丧失方法的实验。首先，我们将表征 使用我们建立的人 ADC 细胞转移扩散和定植的体内模型，研究 GATA6 和 HOPX 在肿瘤发生、远处器官转移和肺 ADC 分化过程中的生物学功能。其次，我们将在基因工程小鼠中开发一个互补模型，以研究 Gata6 和/或 Hopx 的缺失如何在转移进展的不同阶段与 Kras 和 p53 突变配合，以及它们对小鼠气道内源干/祖细胞的相关影响。最后，我们将整合多种方法来阐明 GATA6/HOPX 通路通过控制其靶基因 Hsa-miR-302/367 簇来抑制人类 ADC 转移进展的下游机制。我们的项目预计将揭示控制肺稳态的保守表观遗传网络，以及它们的扰动如何赋予胸部癌多种组织的转移能力。因此，我们提案的总体目标可能为侵袭性转移性肿瘤的起源提供新的线索，并为有转移性疾病风险的肺癌患者提供更准确的诊断方式。 公共卫生相关性：由于肺癌细胞的快速转移扩散，胸部恶性肿瘤是癌症相关死亡的主要来源。我们新颖的多学科方法旨在揭示特定于某些组织细胞类型的分子程序，并表征了这种积极的临床过程。我们相信，该项目将揭示肺部生物学的基本新原理，并为有转移性疾病风险的肺癌患者提供治疗见解。