Pancreatic ductal adenocarcinoma is one of the deadliest forms of cancer in the United States and worldwide. For a number of reasons, pancreatic cancer is a very difficult disease to treat, and there has been limited success in developing new therapeutic agents. Dr. Divya Sood, a Cancer Therapeutics Training Research Fellow in Dr. Andrew Lowy’s lab at the Moores Cancer Center, with their collaborators at Syros Pharmaceuticals, Inc, use a special genomic analysis called super-enhancer profiling to identify potential novel molecular targets for treating pancreatic cancer.
Super-enhancers are large non-coding regions of the genome, consisting of clusters of transcriptional regulators, that drive expression of genes important for governing cell-type differentiation, immune cell functional state, and promotion of tumor development. By collecting primary patient pancreas samples, the authors compare the super-enhancer profiles of normal and cancerous pancreatic tissue, in order to identify the genes that are more strongly super-enhancer tagged in one tissue type or the other. They then use in vitro assays to study the phenotype and function of these differentially tagged genes.
Analysis of the super-enhancers and their associated genes revealed that pancreatic cancer does in fact have a unique epigenetic landscape compared to normal pancreas. They identified regions that were more highly super-enhancer tagged in tumors than in normal pancreas, and additional super-enhancers that were present solely in the tumors.
Amongst the most highly differentially tagged genes was a protein that functions in cytoskeleton dynamics and has been implicated in the progression of gastric and breast cancer, as well as in axon guidance, but has not yet been studied in pancreatic cancer. The authors used wound healing assays and colony formation assays to demonstrate that the loss of this protein, either through the use of a gene knockdown or a small molecule inhibitor, led to decreased migration and decreased proliferation of cells. Additionally, immunohistochemistry demonstrated that this protein is expressed more abundantly at the leading edge of the tumors.
The bottom line: Super-enhancer analysis can define key genes that may drive pancreatic cancer oncogenesis. The protein identified as one of the most highly differentially super-enhancer tagged genes represents a novel potential therapeutic target in pancreatic cancer with implications for the management of cancer progression and metastatic disease. Further validation of this target is ongoing.
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Dr. Divya Sood is a Cancer Therapeutics Training Research Fellow in the lab of Dr. Andrew Lowy, who is Chief of the Division of Surgical Oncology in the Department of Surgery at UC San Diego.
Dr. Divya Sood
Dr. Andrew Lowy