To explore essential molecular features of carcinoid tumors and discover new drug targets, by:
Identifying transcriptional and epigenetic factors that are recurrently dysregulated in human ileal neuroendocrine (carcinoid) tumors.
Characterizing native enteroendocrine (EE) cell precursors that are present in mouse intestinal crypts and likely represent the cells of carcinoid tumor origin.
Identifying and studying key molecular determinants of EE cell proliferation by gain- and loss-of-function approaches.
Intestinal carcinoid tumors originate in sparse mucosal enteroendocrine (EE) cells and epigenetic dysregulation is a likely crucial pathogenic factor, but the cell of tumor origin has never been characterized or isolated. As a result, efforts to define molecular carcinoid pathology are limited by the lack of a normal intestinal EE cell reference to compare against carcinoid tumors and identify key dysregulated pathways. We have found that Bmi1hi mouse intestinal crypt cells are EE precursors that dedifferentiate into proliferating stem cells in response to injury and represent the likely source of intestinal EE (carcinoid) tumors; these cells are readily isolated for molecular and functional analyses. We have also developed a method to produce millions of human EE cells by directed differentiation of intestinal stem cells. These exciting advances offer unprecedented opportunities to discover molecular underpinnings of carcinoid tumors and identify targets for rational therapy. To these ends, we will compare the transcriptome and epigenome of primary human ileal carcinoid tumors with normal human ileal EE cells (Aim 1) and characterize molecular and epigenetic features of Bmi1hi mouse EE precursors in detail (Aim 2). Together, these studies and cross-species comparisons will identify the crucial signals and pathways dysregulated in carcinoid tumors. We will interrogate the functions of the key genes by transfection-mediated gain and CRISPR-mediated loss of function in human ileal EE cells, both in culture and in mouse liver xenografts (Aim 3). The overall goal that unites the three Aims is to identify druggable targets that promote human carcinoid cell survival and proliferation.
NET Research Foundation
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