A Novel Lineage Specific Metastasis Suppressor Pathway in Lung Cancer

描述(申请人提供)：胸部恶性肿瘤的死亡人数超过前列腺癌、乳腺癌和结直肠癌的总和。最常见的肺癌亚型是肺腺癌(ADC)，它可以迅速转移到多个重要器官。尽管最近在肺癌的基因分类方面取得了进展，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范才能正常 动态平衡。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。我们认为这些转录因子协同作用抑制了转移级联反应中的多个生物学步骤。此外，我们假设GATA6和HOPX控制着一种谱系特异性的转移程序，该程序对远端呼吸道上皮细胞和LUG ADC亚型具有选择性。为了研究这一途径，我们将进行实验，利用在体内时空控制的基因功能获得或丧失的方法。首先，我们将描述 利用我们建立的人肺上皮树突状细胞体内转移和定植模型，研究了GATA6和HOPX在肿瘤发生、远处器官转移和肺上皮下树突状细胞分化过程中的生物学功能(S)。其次，我们将在基因工程小鼠中建立一个互补的模型，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突变协同作用，以及它们对小鼠呼吸道内源性干细胞/祖细胞的相关影响。最后，我们将结合多种方法来阐明GATA6/HOPX途径通过控制其靶基因HSA-miR-302/367簇抑制人ADC转移进展的下游机制。我们的项目预计将揭示控制肺内稳态的保守的表观遗传网络，以及它们的扰动如何赋予胸癌向多个组织转移的能力。因此，我们提案的总体目标可能会为侵袭性转移肿瘤的起源提供新的线索，并为有转移风险的肺癌患者提供更准确的诊断方法。

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.