Grant: Project Grant

Pediatric lung cancers are rare but diverse. Pleuropulmonary blastoma (PPB) is the most common pediatric primary lung cancer. It arises during fetal life and occurs in children under 7 years of age. PPB results from the progression of abnormal lung cysts to an aggressive sarcoma with poor survival. It is crucial to correctly recognize PPB early since it is the most curable stage. We produced a mutant mouse line devoid of YY1 function in lung epithelium. YY1 is a transcription factor essential for normal and cancer development. The mutation causes lung cysts as those seen in PPB patients at early stage. Accordingly, less YY1 protein is detected in PPB patients. PPB is associated with mutations in DICER1, an enzyme important for the production of microRNAs. microRNAs negatively control gene expression. How DICER1 and microRNAs act in PPB remains ill-defined. Our data suggested that the low YY1 protein levels detected in PPB are due to abnormal microRNAs caused by the DICER1 mutations. We also showed that the Yy1 mutation in mice affects the expression of key regulators of lung formation and that similar changes are seen in PPB patients. These data led us to hypothesize that reduced expression of YY1 participates in PPB pathogenesis by perturbing the expression of key regulators of lung development. Our objective is to elucidate the role of YY1 in PPB based on our knowledge of the mechanisms of action fulfilled by YY1 during lung formation. We propose to: (1) determine the role of microRNAs in YY1 expression, (2) identify the gene networks controlled by YY1 during lung formation, and (3) test if modulating the levels of YY1 effectors can rescue the cystic lung phenotype of mutant mice. Characterizing the YY1-driven basic mechanisms by which lung development occurs is important for understanding human diseases such as PPB.