Cellular senescence is a stable form of proliferative arrest that acts as a potent barrier to cancer development and may contribute to various age-related pathologies. Initially defined by the phenotype of fibroblasts undergoing replicative exhaustion in culture, senescence can be triggered in many cell types by a range of cellular stresses. The senescence program is controlled by interplay between the Rb and p53 tumor suppressor networks, and senescent cells typically undergo changes in gene expression involving downregulation of growth promoting genes, upregulation of cell cycle inhibitors, and changes in the expression of secreted molecules involved in extracellular matrix production and immune surveillance. This project was inspired by our observation that oncogenic Ras proteins could trigger senescence in primary cells through Rb and p53 dependent mechanisms, thereby preventing malignant transformation. Based on these initial observations, we proposed that this "oncogene-induced senescence" acts as a cellular "failsafe" mechanism to suppress tumorigenesis, a hypothesis that is now supported by numerous animal and human studies. Over the last 10 years, work supported by this project made substantial contributions to our understanding of senescence mechanisms, for example, by characterizing how oncogenes signal senescence, identifying senescence effector mechanisms that enforce a stable cell-cycle arrest, and showing that the impact of cellular senescence on tumor and tissue biology involves the coordinated action of the cell cycle arrest program with a novel form of immune surveillance. The project also defined roles of senescence beyond tumor suppression, showing that senescence could contribute to the outcome of cancer therapy in vivo, and acts in settings beyond cancer, for example, to limit liver fibrosis. In this renewal application, we propose to continue to explore the roles and regulation of cellular senescence, with an increased emphasis on in vivo models and biological contexts beyond cancer. As in the past, we will explore how the Rb and p53 pathways interact to promote senescence;however, new studies on the mechanism and action of NFkB signaling in senescence will be integrated into these efforts. We also will continue to study how senescence regulators impact tumor suppression, but will expand our efforts to include studies on how senescent cells are recognized by components of the innate immune system and the implications the interplay between senescence and the immune system on tissue fibrosis. Our approach interrogates the senescence program at many levels, and incorporates new RNAi technology and in vivo systems developed in our laboratory;these tools enable a seamless integration of mechanistic and biological studies, in vitro and in vivo. We expect our studies to further assemble an important tumor suppressor network that limits cancer development and may contribute to age related diseases, and will begin to identify strategies to modulate senescence for therapeutic purposes.

Public Health Relevance

Cellular senescence is a permanent cell cycle arrest program that has only recently been appreciated to play an important role in preventing cancer development and in limiting wound healing responses, such as fibrosis. By combining a innovative and cost- effective strategies to characterize the roles and regulation of senescence cultured cells and in mice, we will produce insights into natural processes triggered in damaged cells that limits their progression to tumors or stimulates tissue repair following damage. This knowledge will suggest ways in which to modulate senescence for therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016379-15
Application #
8520124
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
1999-07-01
Project End
2014-08-31
Budget Start
2013-09-15
Budget End
2014-08-31
Support Year
15
Fiscal Year
2013
Total Cost
$337,171
Indirect Cost
$152,824
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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