Grant: Project Grant

Non-small cell lung carcinoma is the leading cause of cancer-related deaths worldwide with activation of KRAS signaling being one of the most prevalent oncogenic events. Current efforts to understand the genetic and molecular interactions contributing to KRAS-induced tumors have focused mostly on protein coding genes, leaving the noncoding genome vastly under-explored. We now know that a large fraction of the genome is transcribed and generates thousands of long noncoding RNAs (lncRNAs) that do not encode proteins. Accumulating evidence point to lncRNAs as risk factors frequently dysregulated or mutated in a variety of human cancers. Amongst the few lncRNAs that have been characterized, some were found to affect processes relevant to transformation, such as proliferation and genomic stability. Yet, most studies have been limited to cell line-based assays or remain correlative. Thus, whether lncRNAs contribute to the formation or progression of lung cancer in vivo and how they may affect oncogenic pathways such as KRAS still remains poorly characterized. Recently, downregulation of the lncRNA Tug1 was found to correlate with poor prognosis in human non-small cell lung carcinoma. Our preliminary experiments indicate that loss of Tug1 collaborates with activated KRAS signaling to promote cellular transformation. Using genetically engineered mouse models, we propose to characterize the putative tumor suppressor function of Tug1 in vivo and determine which pathways involved in cellular transformation are affected. We will also decipher its mechanism of action in KRAS-induced lung cancer and use xenograft models to determine whether its function is conserved in human. This project will uncover novel lncRNA-based mechanisms contributing to the formation and progression of lung cancer in vivo. It will also provide potential new therapeutic avenues by revealing new aspects of KRAS signaling, one of the most frequently activated pathway in lung cancer.