The Role of Long Non-coding RNAs in EMT and Cancer Stem Cells

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PROJECT SUMMARY/ABSTRACT Candidate Dr. Jason Herschkowitz began his research career as a graduate student in the laboratory of Dr. Charles Perou at UNC Chapel Hill. His research focus was on a large-scale genomic comparison of human breast cancer subtypes and genetically engineered mouse mammary tumor models. This study showed that although no single mouse model recapitulated all the expression features of a given human subtype, many of the defining characteristics of the human subtypes were conserved among the mouse models providing insight for their preclinical applications. Jason then moved to the Baylor College of Medicine (BCM) as a postdoctoral fellowship in Dr. Jeffrey Rosen's laboratory. There he has concentrated on studying the claudin-low subtype of breast cancer initially identified in his graduate work. Using a unique mouse model, he has determined that claudin-low tumors are enriched for functional cancer stem cells (CSCs) compared to tumors of other subtypes arising in this model. Jason's graduate training has provided him with an expertise in cancer genomics and mouse models. His postdoctoral work has given him the knowledge and skills involved in stem cell research, mammary gland development, and tumorigenesis. Jason's short-term career goals are to now take what he has learned and apply it to the field of long non-coding RNAs (lncRNAs). In order to receive training in this new area, Jason has identified two additional outstanding co-mentors in Dr. Howard Chang and Dr. George Calin. The goal of the next two years is for Jason to receive the additional research training necessary to tackle this new research area as well as valuable career mentorship to prepare him for a successful career as an independent investigator at a highly ranked academic institution. Environment Jason is a postdoctoral fellow in the laboratory of Dr. Jeffrey Rosen in the department of Molecular and Cellular Biology, part of the Dan L. Duncan Cancer Center and the Breast Research Program of the Lester and Sue Smith Breast Center. BCM is an outstanding environment for trainees to develop the necessary skills to become successful independent researchers. The college has exceptional faculty, centers, and state of the art core facilities. BCM is located in the heart of the Texas Medical Center and is walking distance to several outstanding research and clinical institutions including M.D. Anderson Cancer Center, UT Houston Medical School, Rice University, and the Methodist Hospital Research Institute. These institutions serve as additional scientific resources, sources of collaboration, and seminars. Research Gene expression profiling has been used to classify human breast tumors into distinct, clinically- relevant subgroups, including a rare molecular subtype referred to as claudin-low. Compared to tumors of other subtypes, claudin-low tumors have lower expression of tight and adherens junction genes, including claudin 3 and E-cadherin, and higher expression of epithelial to mesenchymal transition (EMT) associated genes. We recently found that claudin-low tumors are enriched for functional CSCs. It has been determined that inducing EMT in human mammary epithelial cells endows them with stem cell-like properties. Together these lines of evidence suggest important molecular and biological links between EMT and the CSC-enriched claudin-low tumors. Recent studies suggest that the majority of the genome is transcribed even though less than 2% of the mammalian genome is occupied by coding regions. These transcripts are called non-coding RNAs (ncRNAs) because they have no protein coding capacity. There has been a great deal of focus on the role of a class of small ncRNAs, called miRNAs, in development and cancer. In contrast, much less is known about the vast majority of transcripts represented by lncRNAs. One recent theme is that many lncRNAs function through interactions with chromatin modifying complexes and control chromatin architecture. While a variety of functional roles for lncRNAs have been implicated in many biological processes, only in relatively few cases have these been well defined. The precise mechanistic details of lncRNA function remain a mystery that needs exploration. As might be expected from the roles of lncRNAs in transcriptional regulation, epigenetic modifications, and development, there is increasing evidence of the misregulation of lncRNAs in cancer. Several groups, including ours, have shown that breast CSCs are more resistant to radiation and chemotherapy compared to non-CSCs. We hypothesize lncRNAs play a critical role in an EMT gene expression program governed in part by RNA-mediated epigenetic regulation leading to resistance to conventional therapies in breast cancer. An improved understanding of the molecular networks responsible for the EMT/CSC phenotype is critical for defining targets for combating the therapeutic resistance of CSCs, which may be especially pertinent to claudin-low tumors. The goal of this project, using several model systems and a strategy for large-scale functional screening, is to first identify and then investigate the mechanisms of action of lncRNAs that regulate the EMT/CSC phenotype of claudin-low breast tumors.