Dr Laureano de la Vega

Stress Responses

Organisms need to be able to adapt to change in order to survive, and certain cellular programs (stress response pathways) have evolved to respond to a dynamic environment. Example of stress responses pathways include p53, NRF2, and HSF1 pathways. Stress responses are by definition acute, and their transient activation help normal cells to cope with cellular stresses. Interestingly, there is a large body of evidence showing that, in contrast to normal cells, cancer cells are constitutively under cellular stress (i.e. DNA damage/replication stress, proteotoxic stress, mitotic stress, metabolic stress, and oxidative stress) and they depend on the sustained activation of cytoprotective stress response pathways to survive.

The essential nature of the stress response pathways in cancer cells makes them attractive targets, and thus, a better understanding of how these pathways are regulated could help identify new ways to modulate stress responses to impair cancer cell survival. In that sense, our lab is focused in obtaining a detailed understanding of stress response pathways and their aberrations in cancer. For that, we are interested not only on key master regulators of stress responses (e.g. NRF2, HSF1 or P53) but as well in the upstream regulatory pathways that modulate their activity (i.e. upstream kinases).

HIPK/DYRK family

Homeodomain-Interacting Protein Kinases (HIPKs) are a subfamily of the Dual specificity tYrosine Regulated Kinase (DYRK) family of kinases. These kinases function as hubs for a wide variety of stress signals, ranging from DNA damage and hypoxia to reactive oxygen species and metabolic stress. HIPK/DYRKs function as integrators for these stress signals and modulate different downstream pathways in order to allow cells to cope with these situations. Different posttranslational modifications modulate the activity and physiological role of HIPK/DYRKs, and the study of how their activity is regulated in different pathophysiological scenarios is an important line of investigation in cancer research.

Based on the literature and on previous studies from the lab it has become apparent that HIPK/DYRKs can play a dual role in cancer; either inducing apoptosis or promoting cell survival. While the pathways involved in their tumour suppressor role are relatively well studied, the underlying mechanisms mediating their pro-survival function(s) are not well characterised. Specifically, we are interested in i) understanding how this family of kinases is regulated in cancer cells; ii) identifying novel HIPK/DYRK-regulated pro-survival/oncogenic pathways and iii) to identify the basis for such functional duality in cancer, as it will inform us in which type of cancer or under which conditions (i.e. initial stages of cancer versus well stablished cancers) these kinases can support cancer cell survival and tumour growth.

Laureano currently teaches on the MRes Cancer Biology Course as a module lead, and on the BSc (Hons) level 3 Molecular Biology module and as a Journal Club leader.