Maintaining epithelial homeostasis is crucial for organismal health since disruption of epithelial homeostasis promotes many human diseases, including cancers. Unnecessary, defective, or potentially harmful cells can be eliminated from epithelia by ?cell extrusion??a process to remove cells from epithelia without disrupting its barrier function. Previous studies have shown that cells can extrude from epithelia either apically or basally. Since the apical side of epithelia faces the outside or lumen, extrusion of cells toward the apical side generally leads to the shedding of extruded cells. In contrast, oncogenic transformation can make cells extrude toward basal side of the epithelia. When these basally extruded cells do not die off, they can spread to stroma and/or other tissues, which can be deleterious to the tissue and organism as a whole. Although basal cell extrusion is a crucial process for maintaining tissue homeostasis and initiating cancer metastasis, its cellular and molecular mechanisms are poorly understood. We have recently established a new Drosophila intestinal model of basal cell extrusion. We discovered that intestinal stem cells expressing oncogenic Ras (RasV12) extruded basally from intestinal epithelia in adult Drosophila. This model provides us a unique opportunity to uncover the fundamental mechanisms impinging on basal-cell extrusion using the state-of-the-art genomic and genetic tools available in Drosophila. With this model, we propose to address a few outstanding questions in the field: (1) we will define the cellular processes required for basal cell extrusion and determine their signaling networks; (2) we will scrutinize another long- standing question that epithelial-mesenchymal transition, a tumor-promoting process, is required for basal cell extrusion; and (3) we will elucidate the role of innate immune cells in the elimination of transformed cells via basal cell extrusion. Discovering the molecular basis underlying basal cell extrusion will help us to learn how to tweak the process to keep epithelia healthy and to prevent tumor metastasis.

Public Health Relevance

Extrusion of transformed cells through the basal side of epithelia is an important cellular process for protecting it from malignant transformation. Nevertheless, the cellular and molecular mechanisms underlying extrusion of transformed cells are poorly understood. The proposed studies, utilizing a new model of basal cell extrusion, will allow us to discover the fundamental mechanisms that govern the process, which, in turn, will promote our knowledge on how to keep epithelia healthy and how to prevent cancer metastasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM128752-03
Application #
9973105
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Maas, Stefan
Project Start
2018-08-01
Project End
2023-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195