A Novel Lineage Specific Metastasis Suppressor Pathway in Lung Cancer

描述（由申请人提供）：胸部恶性肿瘤导致的死亡人数超过前列腺癌、乳腺癌和结直肠癌的总和。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。尽管最近在肺癌的遗传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。哺乳动物肺是复杂的器官，其需要各种上皮细胞类型的特化以进行适当的细胞分化。 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ADC复发之间的独特联系。特别地，我们发现了与细胞命运转录因子GATA 6和HOPX相关的转移抑制途径。我们认为，这些转录因子的合作，以抑制多个生物步骤的转移级联。此外，我们假设GATA 6和HOPX控制一个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，我们将进行实验，利用时空控制的基因获得或功能丧失的方法在体内。首先，我们将描述 GATA 6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，使用我们建立的人ADC细胞转移性播散和定殖的体内模型。其次，我们将在基因工程小鼠中开发一种互补模型，以研究Gata 6和/或Hopx的丢失如何在转移进展的不同阶段与Kras和p53突变合作，以及它们对小鼠气道内源性干/祖细胞的相关影响。最后，我们将整合多种方法来阐明GATA 6/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保守的表观遗传网络，控制肺内稳态，以及他们的扰动如何赋予胸部癌症转移到多种组织的能力。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。

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.