Biological Insights Into Senescence and Cancer

Abstract

Cellular senescence is a stress-activated differentiation pathway that causes proliferation arrest governed by two powerful tumor suppressor pathways, USP28-TP53-CDKN1A and CDKN2A-RB. Senescent cells exhibit a pro-inflammatory secretory program termed the senescence-associated secretory phenotype (SASP) that is composed of chemokines, cytokines, growth factors, and proteases. SASP induction is independent of TP53 and RB function and its role in cancer has not been fully elucidated. The second chapter of this dissertation describes our studies to understand SASP and its role in cancer. We genetically targeted the master regulator of SASP, GATA4, and found that SASP functions as a non-cell autonomous tumor suppressor mechanism. We show that SASP is tumor suppressive in mouse models of cancer using both deletion and overexpression contexts. SASP-dependent tumor suppression requires the immune system, specifically CD8 cytotoxic T cells, to suppress tumor growth. Human tumors deficient in GATA4 have reduced lymphocyte infiltrates, suggesting that our findings may contribute to understanding tumor evolution in human cancers. The third chapter of this dissertation describes a genome-scale genetic screening approach to identify novel regulators of senescence. We identify the zinc-finger protein ZNF292 as a previously unknown player in senescence. The fourth chapter of this dissertation describes a genome-scale genetic screening approach to identify the mechanism by which GATA4 regulates the cell cycle. We tentatively identify the Hippo pathway as a mediator of GATA4-dependent cell cycle arrest.