LncRNAs in Cancer: What, Where and How?
Mammalian genomes transcribe thousands of long noncoding RNAs (lncRNAs), often with exquisite cell type and cell state specificity. Despite garnering enormous attention in recent years, the functions and mechanisms of action of lncRNAs remain poorly understood, in part due to the scarcity of carefully designed genetic models. With a growing appreciation that the expression of lncRNAs is frequently deregulated in disease states, including cancer, there is an unmet need to gain a deeper understanding of the in vivo biology of this novel class of RNAs.
To unravel the complexities of lncRNAs, research in the Dimitrova lab focuses on a subset that are directly induced by the transcription factor p53. As components of arguably the most important tumor suppressor pathway in mammals, p53-regulated lncRNAs are expected to influence the expression of proteins in the p53 pathway and to play key roles in the physiological response to stress and in tumor suppression. We use precise genetic engineering in mice and cell lines to interrogate the functions of p53-regulated lncRNAs as well as to identify the critical domains required for their activities. The goal of these efforts is to elucidate unifying principles that can be used to classify lncRNAs into functional and mechanistic subgroups. Insights derived from these studies will serve as an entry point to assess the broader significance of lncRNAs in tumor development in vivo.
1. The roles of lncRNAs in transcriptional and translational control of cancer pathways. Many lncRNAs have been implicated in transcriptional control of nearby or distant genes. Others have been implicated in regulating mRNA translation. Focusing on specific lncRNAs downstream of the p53 tumor suppressor network, we investigate the mechanisms and importance of these regulatory activities using CRISPR-based genetic and epigenetic approaches.
2. The roles of lncRNAs in dictating specific outcomes in the p53 pathway. We are interested in understanding how lncRNAs participate in decision-making processes in complex transcriptional networks, such as the p53 tumor suppressor pathway. Our studies implicate lncRNAs in promoting alternative outcomes of p53 activation. Our research aims to elucidate their contribution to the p53 tumor suppressor pathway, determine their direct targets of regulation, as well as identify interacting proteins that mediate their function. This set of experiments will thus reveal the extent to which lncRNAs mediate physiological outputs in the p53 pathway.
3. The contribution of lncRNAs to tumor suppression in vivo. Despite emerging evidence that genetic and epigenetic alterations in non-coding regions can shape cancer development, the contribution of lncRNAs to tumorigenesis in vivo remains vastly understudied. To fill this gap, we study how altered expression of regulatory lncRNAs influences tumor development in mouse models relevant to the human disease. We employ the oncogenic K-ras-driven autochthonous mouse model of lung adenocarcinoma, which is particularly well-suited for these studies as it is highly amenable to loss- and gain-of-function manipulations in vivo and closely mirrors the human disease. Insights from these studies will inform how deregulation of regulatory lncRNAs influences the different stages of cancer development in vivo.