Epigenomic Analysis of Intestinal Neuroendocrine Cells and the Epigenetic Basis of Neuroendocrine Tumors
Researcher: Ramesh Shivdasani, MD, PhD Location: Dana-Farber Cancer Institute State: Massachusetts Year: 2013 Status: Finished
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To study how epigenetic regulation controls the process by which a stem cell becomes a neuroendocrine cell and to identify how changes in epigenetic regulation can promote development of neuroendocrine tumors.
With prior funding from CFCF, the Shivdasani lab has made significant progress in understanding the cell of origin for intestinal neuroendocrine tumors. Intestinal stem cells have the capacity to replicate indefinitely or to become any of many different types of intestinal cells. Dr. Shivdasani’s laboratory studies how these gastrointestinal stem cells make the decision to stop behaving like a stem cell and instead to differentiate into a neuroendocrine cell that might someday become a neuroendocrine tumor cell.
To build on prior progress, CFCF has awarded a second grant to Dr. Shivdasani to study how epigenetic regulation controls the process by which a stem cell becomes a neuroendocrine cell and to identify how changes in epigenetic regulation can promote development of neuroendocrine tumors.
Epigenetic regulators determine which genes are turned on or off under specific conditions in a cell. While genes contain the instructions for assembling proteins, it is through epigenetic regulation that cells are able to control whether or not these proteins are actually produced.
Epigenetic regulation controls the processes by which intestinal stem cells decide between remaining a stem cell and differentiating into a neuroendocrine cell. Epigenetic regulation has recently been identified as a potential cause of neuroendocrine tumor development as mutations in epigenetic regulating genes have been identified in neuroendocrine tumors.
Elucidate key epigenetic regulatory steps in differentiation of intestinal stem cells into neuroendocrine cells.
Determine how epigenetic regulation controls proliferation and differentiation of neuroendocrine cells.
Identify new genes and pathways to target for treatment of patients with neuroendocrine tumors
Intestinal neuroendocrine tumors arise from rare hormone secretingprogenitor cells that in turn arise from self-renewing stem cells. In current views, a key cell population in cancers, including intestinal and pancreatic neuroendocrine tumors, manifests the stem-cell properties of lifelong self-renewal, incessant replication, and immaturity. Therefore, it is very important to understand the normal basis for these properties and how individual cancers adopt them. Such understanding will inform rational approaches toward cancer prevention and therapy.
Mutations in protein-coding genes drive cancer development and progression. Knowledge of such mutations in several cancers has identified prime molecular targets for therapies that are starting to extend patients’ lives. Mutations affect the primary DNA sequence in the single cell that eventually turns cancerous. However, the bulk of DNA in human cells does not encode proteins; much of the genome is devoted to ensuring tight control of protein-coding genes, specifically, in determining whether they will be turned on or off. This process is known as epigenetics and its vital role in normal and cancer cells is coming into sharper focus, for two reasons.
First, epigenetics control cell differentiation, the process by which stem cells make the choice between indefinite replication and maturing into a committed cell type such as an intestinal or pancreatic neuroendocrine cell.
Second, mutations in epigenetic regulatory genes are found in many cancers, including neuroendocrine tumors, pointing to altered gene regulation as a second key driving force. In fact, the few mutations identified to date, in pancreatic neuroendocrine tumors, occur in genes that control other genes (epigenetic regulators). However, we know so little about normal epigenetic control that it is difficult to know where to begin to translate these seminal discoveries into useful treatments for patients.
To narrow this gap in knowledge, here I propose timely studies to investigate the normal epigenetic control of intestinal stem and enteroendocrine progenitor differentiation and to characterize the epigenetic basis of neuroendocrine tumorigenesis.
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