How cells communicate to coordinate their growth is a fundamental question in biology that is important to many aspects of medicine and health, including organ regeneration and transplantation, stem cell biology, and cancer. Here we address how a signaling pathway we recently uncovered functions during competitive interactions between cells in developing and remodeling tissues, in which normally viable cells are killed and eliminated when they grow next to "winner" cells with higher metabolic rates. We propose experiments in Drosophila to take advantage of the powerful genetic and molecular tools available, which are unparalleled in higher animals. We will use genetic analysis of mutants, somatic clonal techniques, and molecular analysis to achieve two specific aims:
Aim 1, to investigate the mechanistic role of the signaling pathway in "loser" cells and discover target genes of the pathway that function as effectors of cell competition, and Aim 2, to determine how a putative ligand mediates communication between "loser" and "winner" cells and leads to activation of the signaling pathway in loser cells. These studies will reveal mechanisms underlying interactions between cells in growing epithelia that may be valuable for improving the health and care of humans. In addition, they will expand our understanding of fundamental aspects of cell-cell communication during growth.

Public Health Relevance

Our previous work using Drosophila as a model system has demonstrated that competition is induced between neighboring cells when they grow with different metabolic rates. This process ensures tissue plasticity during growth and development. Our recent experiments have implicated a novel signaling pathway in the competition process, and here we aim to use the unparalleled power of Drosophila molecular genetics to understand its role in the cellular events involved in competition, such as overgrowth, cell death and cell-cell communication. Cell competition has remarkable similarities to the early stages of cancer, thus we anticipate that this work will aid in the identification of markers distinguishing early cancer cells from their wildtype neighbors. In addition, it will enhance our knowledge of mechanisms of tissue plasticity and fitness selection. Furthermore, our understanding of the basic biological properties of cell communication during growth will be expanded.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD067918-02
Application #
8232014
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Mukhopadhyay, Mahua
Project Start
2011-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$201,250
Indirect Cost
$76,250
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
de la Cova, Claire; Senoo-Matsuda, Nanami; Ziosi, Marcello et al. (2014) Supercompetitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability. Cell Metab 19:470-83
Meyer, S N; Amoyel, M; BergantiƱos, C et al. (2014) An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 346:1258236