Project No. 2333
Dr Jerome Korzelius – University of Kent
Dr Nahuel Villegas- Vivan Therapeutics
Adult intestinal stem cells (ISCs) play a critical role in the maintenance of our intestine and dysregulation of stem cells is one of the main causes of diseases such as cancer.
An understudied mechanism is the role of the surrounding epithelial cells and their function as a niche for the stem cells and which signals either promote or inhibit ISC proliferation. Understanding the role of the ISC micro-environment will help us better understand the regulation of adult stem cells in both healthy and diseased tissues.
The Drosophila intestine has been a cost-effective and genetically tractable model for studying ISCs. The Drosophila intestine, like its mammalian counterparts, is maintained by a population of Intestinal Stem Cells (ISCs) that divide and maintain the intestinal epithelium. Major signaling pathways controlling ISC division and differentiation are conserved between flies and mammals. Similar to mammals, overexpression of the EGFR/Ras pathway components combination with loss of the negative Wnt-pathway regulator APC will lead to tumorous outgrowths. Vivan Therapeutics has been using the Drosophila system to test the effect of different drug combinations on custom-built colorectal cancer patient avatars harboring the same driver mutations as seen in the patient. Their platform allows for high-throughput survivability screening of different drug combinations and/or genetic manipulations.
In this project we will separately manipulate stem cell overgrowth and the surrounding epithelium to address the role of the surrounding epithelium as a niche for ISC proliferation. In collaboration with Vivan Therapeutics, we will build models for ISC overgrowth by manipulating different growth-promoting pathways in parallel. We will combine this with downregulation of candidate genes in the surrounding differentiated enterocytes (EC) and endocrine cells (EE) to identify novel niche factors that exacerbate or inhibit ISC overgrowth. We employ a focused list of secreted molecules that are expressed in the intestine in these cell types and check the effect of knockdown or overexpression for enhancement or suppression of ISC overgrowth. We will use the Vivan automated survivability platform for the screening. Selected candidates will be followed up in vivo in both the Drosophila intestine as well as human intestinal organoid culture to determine their mode of action.