Juan Carlos Acosta Cobacho (IP)

  • c/ Albert Einstein, 22 (PCTCAN) Edificio IBBTEC 39011 Santander
  • juan.acosta@unican.es
  • (+34) 942 203937
  • Tumour suppression, cellular senescence, SASP and innovative therapies
  • Principal Investigator
  • Cancer
  • Department of Cell & Molecular Signalling

​After his graduation in pharmacology (mPharm) by the University of Salamanca in 1997 in Spain, Juan Carlos Acosta moved to Santander, Spain, to the laboratory of Professor Javier Leon at the department of Molecular Biology of the University of Cantabria to complete his PhD investigating the functional interactions between p27 and MYC in erythroid differentiation of leukaemia cells. In 2006 he moved to London to complete a postdoctoral training at the laboratory of Jesus Gil at the MRC Clinical Sciences Centre at the Imperial College, working in several aspects of the regulation of senescence and the identification of new tumour suppressor pathways. During his postdoctoral investigation, Juan Carlos contributed critically to discovering the Senescence Associated Secretory Phenotype (SASP), its mechanism of activation and its paracrine effects, and the elucidation of the mechanism of activation of the INK4-ARF tumour suppressor locus by oncogenic RAS. In 2013 obtained a prestigious Chancellor's Fellowship from the University of Edinburgh and a CRUK Fellowship, which allowed him to establish his independent research group at the Cancer Research UK Edinburgh Centre in the MRC-Institute of Genetics and Molecular Medicine (now Institute of Genetics and Cancer) at the University of Edinburgh. His research focused on the mechanisms regulating the SASP, the interrelation between signalling from innate immune sensors such as the inflammasome or toll-like receptors and cellular senescence, and the impact of the nuclear reorganization in senescence on the regulation of transcriptional programs. In September 2021, Juan Carlos was appointed Research Professor of the Spanish Research Council (CSIC) and has since then relocated his research group at the Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC) at the University of Cantabria where he leads a research team with interest on the SASP, its activation mechanisms, interrelation with the immune system, pathophysiological consequences and natural function. His work has been published in top journals such as CellNat Cell Biol., Science Adv., or Genes & Dev, he is frequently invited to speak at prestigious conferences, has been awarded competitive awards and funding such as the CRUK Fellowship, sits in top funding review committees, and peer-reviews for impactful journals and research funding institutions.

Our research aims to study the molecular mechanisms controlling cellular senescence to reveal new targets for cancer and ageing treatments, and to address the outstanding fundamental question about the origin and function of the senescent cell state.

 

Cellular senescence is a terminal stress response that impairs the propagation of mutated and damaged cells. It is characterised by a robust cell cycle arrest and the induction of a complex pro-inflammatory response, the senescence-associated secretory phenotype (SASP). Activating cellular senescence in response to oncogenic activation (oncogene-induced senescence) functions as a potent tumour suppressor response impairing malignant transformation. However, the accumulation of senescent cells in tumours because of anti-cancer therapies, oncogenic activation, or ageing, can, in the long-term, facilitate cancer progression through the SASP. Thus, as the new therapeutic advances improve and extend the survival of cancer patients, novel strategies controlling the adverse effects of accumulating senescent cells in tumours are urgently needed. Besides, senescent cells accumulate during organismal ageing, behaving as "zombie-cells" that negatively affect the surrounding tissue through the pro-inflammatory SASP, promoting ageing and age-related diseases. Indeed, eliminating senescent cells in transgenic mouse models improves organismal ageing, indicating a fundamental role of senescent cells in such a process. Thus, we aim to identify molecular mechanisms controlling the SASP to design strategies to mitigate the side effects of accumulating senescent cells in cancer and during aging.

 

In recent years, therapies to target senescent cells (senotherapies) in cancer and ageing by, for example, using small chemical compounds exploiting senescent cell vulnerabilities that result in the specific killing of senescent cells (senolytics), have been shown effective in treating ageing and age-related diseases in preclinical models, and clinical trials are undergoing to assess their therapeutic potential in humans. Furthermore, two-punch anti-cancer therapeutic strategies inducing cellular senescence in cancer cells, followed by interventions to eliminate those senescent cancer cells (e.g. senolytics), have been proposed as a new rationale for anti-cancer therapies. However, most senolytic target pathways are mostly inactivated in human cancer (e.g. p53), so unique mechanistic insight is necessary to identify senolytic pathways to target senescent cancer cells in tumours. In our group, we discovered that receptors of the innate immune systems (known as pattern recognition receptors) are in the core machinery regulating cellular senescence and the SASP. Specifically, we have shown that innate immune signalling through inflammasomes (caspase-1 and -4) and toll-like receptors (TLR2) are critical for SASP activation. We propose manipulating those pathways to activate selective immune responses and inflict inflammatory cell death in targeted cancer cells using two-punch strategies as an exciting new prospect in the anti-cancer arsenal.

 

Our primary specific research aims are:

 

  1. To reveal new molecular mechanistic insight about the regulation of cellular senescence and the senescence-associated secretory phenotype (SASP)
  2. To characterise the innate-immune identity, origin, and function of the senescent cell state.
  3. To identify new senescent cell vulnerabilities to engineer innovative anti-cancer and anti-ageing therapies based on cellular senescence manipulation.

 

Our group has been vital in discovering the SASP and its dependency on innate immune signalling, and in unravelling transcriptional programs upon senescence-associated nuclear stress and chromatin organisation, resulting in highly cited publication in journals such as Cell, Nature Cell Biology, Genes & Development or Science Advances. We use high-throughput approaches (e.g. proteomics, transcriptomics, metabolomics) combined with focused phenotypic screens (e.g. loss of function genetic RNAi or CRISPR screens, and small chemical compounds) to identify critical functional candidate genes and pathways regulating cellular senescence and the SASP, state of the art molecular and cellular biology methods to characterise their mechanism of action, and preclinical animal models and analysis of human samples to investigate their relevance and functionality in vivo