Cell Proliferation

“Senescence influences multiple biological processes including aging and cancer”

Cellular senescence is a highly stable cell cycle arrest that limits the replication of aged or damaged cells. Senescence can be triggered by replicative exhaustion, oncogene activation or chemotherapeutic drugs. As a consequence, senescence influences the outcome of physiological processes such as aging, development, wound healing, fibrosis and 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. Senescent cells not only exit cell cycle but also undergo profound changes in their transcriptional program, chromatin organization, metabolism and secretome. In particular, the senescence-associated secretory phenotype (SASP) mediates many of the patho-physiological effects exerted by senescent cells.

The goal of our research program is to understand the molecular mechanisms behind the implementation and regulation of senescence. To this end, we use different human primary cell systems, including IMR90 ER:RAS cells as an inducible system of oncogene-induced senescence. Our experimental approaches integrate information from shRNA functional screenings, cellular and molecular biology, high-throughput microscopy, genomics and proteomics that we aim to translate to disease-relevant mouse models.

There are three general questions questions that we are aiming to address:

  • What are the epigenetic mechanisms controlling senescence?
  • What are the regulation, composition and functions of the senescence secretome?
  • How can we target senescent cells for therapeutic benefit in cancer and aging?

Overall, we expect that our research would result in a better knowledge of how senescence impacts aging, cancer and other diseases, opening possibilities to manipulate it for therapeutic advantage.

Cell Proliferation

Senescent cells express a complex secretome that mediate multiple cell autonomous and non-cell autonomous functions. IMR90 ER:RAS cells undergoing oncogene-induced senescence (OIS) express IL-8 (red) and IL-6 (green).

Selected Publications

Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, Wolter K, Pombo J, Irvine EE, Innes AJ, Birch J, Glegola J, Manshaei S, Heide D, Dharmalingam G, Harbig J, Olona A, Behmoaras J, Dauch D, Uren AG, Zender L, Vernia S, Martínez-Barbera JP, Heikenwalder M, Withers DJ, Gil J. (2019). Cardiac glycosides are broad-spectrum senolyticsNature Metabolism doi:10.1038/s42255-019-0122-z

Georgilis A, Klotz S, Hanley CJ, Weirich B, Morancho B, Herranz N, Leote AC, Carroll T, Dharmalingam G, Wee KB, Mellone M, Guccione E, Arribas J, Barbosa-Morais NL, Heikenwalder M, Thomas GJ, Zender L and Gil J. (2018). PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell, 34, 85-102.

Aarts M, Georgilis A, Beniazza M, Beolchi P, Banito A, Carroll T, Kulisic M, Kaemena DF, Dharmalingam G, Martin N, Reik W, Zuber J, Kaji K, Chandra T, Gil J. (2017). Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence. Genes & development 31(20), 2085-2098.

Tordella L, Khan S, Hohmeyer A, Banito A, Raguz S, Martin N, Dhamarlingam G, Carroll T, Klotz S, Deswal S, García-Escudero R, Zuber J, Zender L, Gil J. (2016). SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer. Genes & development 30(19), 2187-2198.

Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martínez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, Gil J. (2015). mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nature cell biology 17(9), 1205-1217.

Acosta JC, Banito A, Wuestefeld W, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Mindaugas A, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman G, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature cell biology 15(8), 978-990.

Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d’Adda di Fagagna F, Bernard D, Hernando E, Gil J. (2008). Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133(6), 1006–1018.