Cellular senescence is a stress response induced by oncogene activation, chronic inflammation, telomere erosion or DNA damage. Senescent cells activate a dynamic transcriptional programme leading to stable cell cycle exit, chromatin reorganization, metabolic reprogramming and the establishment of a senescence-associated secretory programme (SASP). Acute induction of senescence is a physiological response that limits fibrosis and acts as a potent tumour suppressor mechanism. However, the abnormal accumulation of senescent cells contributes to ageing and many diseases, including cancer. Recently, strategies aimed to selectively eliminate senescent cells (senolytic therapies) have been shown great promise for the treatment of a wide-range of diseases.
The goal of my laboratory is to elucidate the molecular mechanisms that implement and regulate senescence. We intend to exploit this knowledge to devise novel strategies that target senescence in age-related pathologies, especially cancer. To investigate senescence, we combine high-throughput screens and mechanistic analyses in cell culture, with in vivo analyses in mouse models. We then analyse clinical samples to uncover the relevance of our observations for human disease.
My research has two overarching aims:
(1) Uncover novel (epi)genetic mechanisms controlling senescence. To this end, we use functional (CRISPR, RNAi and drug) screens, proteomic and genomics to identify trans factors and cis elements that control senescence and elucidate how they function.
(2) Investigate how the SASP mediates the effects of senescence. We approach this by performing screens to discover regulators and functions of different subsets of the SASP (e.g. pro- inflammatory or fibrotic) and use novel mouse models to uncover the roles of the SASP in ageing and disease.
Connecting both aims, we look for vulnerabilities of senescence. We are actively collaborating with several companies to pursue novel ways to target senescence cells. By better understanding how senescence is regulated and implemented, we expect that our research will inform therapies that harness senescence in cancer and ageing.
Gil J, 2023, The challenge of identifying senescent cells, Nature Cell Biology, ISSN:1465-7392
White MEH, Gil J, Tate EW, 2023, Proteome-wide structural analysis identifies warhead- and coverage-specific biases in cysteine-focused chemoproteomics, Cell Chemical Biology, Vol:30, ISSN:2451-9456, Pages:828-838.e4
et al., 2023, Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer, Cancer Cell, Vol:41, ISSN:1535-6108, Pages:1242-1260.e6
Gil J, D’Ambrosio M, 2023, Reshaping of the tumor microenvironment by cellular senescence: an opportunity for senotherapies, Developmental Cell, Vol:58, ISSN:1534-5807, Pages:1007-1021
Isima N, Gil J, 2023, Spurious transcription may be a hallmark of aging, Nature Aging, Vol:3, ISSN:2662-8465, Pages:374-375