Preventing benign lesions from progressing to full-blown malignant transformation remains a top priority in the field of cancer therapy. An increasingly attractive strategy to enhance the barrier to malignancy is the induction of cellular senescence, a stable form of growth arrest. Physiological stresses that cause senescence include DNA damage and oncogene activation. Termination of cell division decreases the cells? tumor-initiating potential. Although senescent cells no longer divide, they remain metabolically active and secrete a defined set of growth factors, cytokines, and proteases, collectively termed the senescence-associated secretory phenotype (SASP). These factors are believed to reinforce the senescent phenotype, induce neighboring cells to senesce, and recruit immune cells to clear away damaged tissue. Therefore, the SASP may enhance the tumor-preventing potential of senescent cells. In stark contrast, many SASP factors have known tumorigenic properties, and have been demonstrated to increase cell proliferation and motility. In addition, SASP-mediated immune cell recruitment can create an inflammatory environment that benefits tumor growth. Therefore, whether senescence induction ultimately drives or prevents cancer remains unclear. Recent studies have indicated that the SASP factor IL-1? acts as an upstream regulator of the SASP, as it is necessary and sufficient to induce specific SASP factor expression. However, the mechanisms that lead to senescence-induced IL-1? activation remain largely unclear. In addition, the in vivo effect of the SASP is poorly understood, as it has been difficult to study the effects of the SASP independently of other senescence-associated phenotypes, such as cell-cycle exit. The goal of this proposal is to explore the mechanisms that lead to IL-1? activation, and to study the effects of SASP abrogation on cancer initiation and progression. In particular, I will investigate the effects of IL-1? deletion in a mouse model of hepatocellular carcinoma (HCC). A majority of HCC cases arise from chronic liver injury and constant tissue regeneration. It has been demonstrated that hepatic stellate cells (HSCs) become activated upon injury, and later senesce to prevent excessive fibrosis and hepatocyte proliferation during tissue repair. Therefore, fibrosis- induced HCC is an ideal model to study the effects of the SASP on cancer progression.
The aims of this proposal include (i) elucidate the molecular pathways that lead to IL-1? activation in senescent cells, and (ii) investigate the specific role of IL-1? and the SASP in fibrosis and HCC. The long-term goal of this project is to uncouple the effects of the SASP in cancer progression from that of cell-cycle exit. Doing so will provide insight into the therapeutic potential of SASP manipulation in cancer patients.

Public Health Relevance

Thoughcellularsenescenceactsasabarriertocancerprogressionbypreventingproliferationofdamagedcells, the factors secreted from senescent cells may paradoxically enhance tumor progression. Our studies will enhance our understanding of the senescence-associated secretory phenotype (SASP) and determine the therapeutic potential of senescence induction or SASP manipulation in cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA206387-02
Application #
9419704
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2017-02-01
Project End
2020-02-29
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10010