Advanced age is the major risk factor for cancer, particularly epithelial cancers. However the fundamental mechanisms underlying the dramatic increase in malignancies later in life remain largely unknown, impeding the development of interventions that prevent or attenuate late-life tumorigenesis. It has long been speculated that senescent cells, which accumulate with aging in many tissues and organs, stimulate the development and dissemination of cancer cells. At first glance, this seems paradoxical because cellular senescence is widely recognized as a crucial anticancer mechanism that prevents the growth of cells at risk for neoplastic transformation. However, recent evidence from in vitro studies supports the idea that cellular senescence may stimulate tumorigenesis by creating a pro-tumorigenic milieu. Senescent cells develop a complex phenotype, termed the senescence-associated secretory phenotype (SASP), in which they secrete high levels of numerous growth factors, cytokines, and proteases. It is thought that this secretome disrupts the architecture and functionality of neighboring cells in the tissue and creates a microenvironment that is permissive for the proliferation and dissemination of neoplastic lesions. The critical barrier to testing this idea in vivo has been the lack of a mouse model that allows for selective elimination of senescent cells. We made use of a biomarker for senescence, p16Ink4a, to generate a novel transgene, INK-ATTAC, which removes p16Ink4a-positive senescent cells upon administration of a synthetic drug. Using this and other mouse models, we will test the central hypothesis that cellular senescence is causally implicated in tumor development and that removal of senescent cells, or key malignancy-associated factors that they secrete, will have a profound tumor protective effect. We propose three specific aims. In the first aim we will determine the extent to which late-life clearance of senescent cells inhibits the development and metastasis of lung and breast cancer. In the second aim, we will establish the nature and consequences of the secretory phenotypes of senescent cells accumulating naturally in different mouse tissues with aging. In the third aim, we will dissect the mechanism by which senescent cells drive tumorigenesis by knocking out individual pro-tumorigenic SASP components specifically in senescent cells and then measuring the effect on mouse mammary gland tumorigenesis. The overall impact of this project is that it will critically test the longstanding untested hypothesisthat senescent cells promote tumorigenesis, address key fundamental questions about naturally occurring senescent cells, identify key components of the SASP that promote tumor development and/or metastasis, and test the entirely novel concept of targeting senescent cells or key elements of the SASP as an anti-cancer therapeutic strategy.
Whether and how senescent cells that accumulate with age promote the development of late-life tumors is one of the major open questions in the fields of cancer and aging research. We can address this question now that we have a novel transgenic mouse model in which we can inducibly kill senescent cells. The proposed research is relevant, as it will develop knowledge that will ultimately improve cancer treatment.
|Baker, Darren J; Childs, Bennett G; Durik, Matej et al. (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184-9|
|Childs, Bennett G; Baker, Darren J; Wijshake, Tobias et al. (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354:472-477|
|Demaria, Marco; Desprez, Pierre Yves; Campisi, Judith et al. (2015) Cell Autonomous and Non-Autonomous Effects of Senescent Cells in the Skin. J Invest Dermatol 135:1722-1726|
|van Deursen, Jan M (2014) The role of senescent cells in ageing. Nature 509:439-46|
|Childs, Bennett G; Baker, Darren J; Kirkland, James L et al. (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15:1139-53|
|Demaria, Marco; Ohtani, Naoko; Youssef, Sameh A et al. (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31:722-33|