The overall goal of this research is to elucidate the mechanisms that underlie tissue homeostasis during growth and to understand how this process goes awry in human diseases such as cancer. We and others have shown that genetic heterogeneity within growing tissues can lead to competitive interactions that eliminate the weaker population and stimulate expansion of the stronger. A guiding principle of our work is that such competition functions in a homeostatic role to eliminate cells that are potentially dangerous to the tissue and animal. We hypothesize that incipient cancer cells exploit this mechanism to gain an advantage and overtake tissues. Our preliminary data indicate that the death of wild-type cells stimulates the proliferation of the high-Myc cells via production of secreted cytokines and/or growth factors. Here, we propose studies to investigate our recent discovery that an NF?B transcription factor, four different Toll related receptors, and a conserved cytokine - all components of the innate immune system - mediate the competitive cellular interactions between cells of different fitness, and trigger the death of the less fit cels. However, critical molecular mechanisms and targets of this pathway remain to be defined. This work has the potential to elucidate essential molecular and cellular events that determine whether pre-cancerous cells will be eliminated from growing tissues or are able to establish themselves and progress into fully neoplastic tumors.

Public Health Relevance

We propose to use a novel Drosophila model of pre-malignant cancer to investigate an innate sensing mechanism that used by pre-cancerous cells to kill normal neighboring cells and expand their territory. We hypothesize that this mechanism is used by cancer cells at a very early stage in tumorigenesis. This work should have important implications for targeting incipient cancer cells before they become frankly tumorigenic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA192838-04
Application #
9380958
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Howcroft, Thomas K
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032