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The Role of Elimination of Senescent Cells in Cancer Development

Objective

Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells.
The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells.
The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.

Call for proposal

ERC-2012-StG_20111109
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Host institution

WEIZMANN INSTITUTE OF SCIENCE
Address
Herzl Street 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
Administrative Contact
Gabi Bernstein (Ms.)
Principal investigator
Valery Krizhanovsky (Dr.)
EU contribution
€ 1 500 000

Beneficiaries (1)

WEIZMANN INSTITUTE OF SCIENCE
Israel
EU contribution
€ 1 500 000
Address
Herzl Street 234
7610001 Rehovot

See on map

Activity type
Higher or Secondary Education Establishments
Administrative Contact
Gabi Bernstein (Ms.)
Principal investigator
Valery Krizhanovsky (Dr.)