Molecular Oncology Programme

Tumour Suppression Group

Group Leader:  Manuel Serrano
Research highlights
New tumour markers for the prognosis of head and neck cancer

Head and neck cancers include a heterogeneous group of tumours located in the oral cavity, pharynx and larynx. The survival rate of patients with this pathology has hardly improved over the last decade. Stratification of patients has been limited, until now, to a clinical classification and not a molecular one. Analysis of patients ’ biopsies showed that about half of them possess high levels of the p21 protein as well as mTOR activation. We have unravelled the molecular mechanism by which p21 levels are linked to the activity of mTOR (FIGURE 1). When the mTOR protein is inactive, it dictates the degradation of p21, and, conversely, when mTOR is active, p21 becomes stable. The presence of both markers, active mTOR and high levels of p21, predict a less aggressive evolution of the disease. This may help in choosing from amongst different therapeutic options for these patients.

Antioxidant defences delay ageing and age-related diseases

Accumulation of cell damage plays an important role in ageing. There is no clear answer about which types of cellular damage are more relevant for ageing. Although the accumulation of oxidative damage with ageing is undisputed, the large majority of attempts to prove that oxidative damage is relevant for ageing have failed. All these attempts, however, have manipulated only one component of the complex network of antioxidant defences. In contrast to these previous attempts, we have approached this issue by increasing the levels of NADPH, a simple co-factor required for almost all antioxidant reactions and whose levels are known to determine the global antioxidant capacity of cells. To achieve this, we generated transgenic mice with an increased expression throughout their bodies of glucose-6-phosphate dehydrogenase (G6PD), one of the most important enzymes for the production of NADPH. We found that G6PD transgenic mice have overall higher levels of NADPH and, consequently, a better protection against oxidative damages. Importantly, these mice are not predisposed to cancer and, indeed, have a modest increase in longevity. These observations point to a novel strategy to delay ageing-related diseases, including cancer.

Senescent cells provide critical signals for cellular reprogramming

The mechanisms involved in the reprogramming of differentiated cells inside a living organism remain to be elucidated. Senescence is a cellular response to damage characterised by an abundant production of cytokines and other secreted factors that, together with the recruitment of inᴀammatory cells, results in tissue remodelling. We have shown that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4 and cMYC (OSKM) triggers two divergent cellular outcomes : most cells undergo senescence, while other cells undergo reprogramming, both occurring in close physical association. OSKM-induced senescence requires the tumour suppressor locus Ink4a/Arf, which, via the production of the cytokine IL6, creates an optimal tissue environment for in vivo reprogramming. We concluded that tissue injury or ageing, through cellular senescence and cytokine IL6, favour in vivo reprogramming by OSKM (FIGURE 2). These findings could be relevant for tissue repair and open new strategies to manipulate reprogramming in vivo.