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Molecular Oncology Programme

Metabolism and Cell Signaling Group

Group Leader:  Alejo Efeyan
Research highlights
Nutrient signalling in B lymphocytes

One of the most rapid proliferation bursts in mammalian cells is that of B lymphocytes upon encountering certain pathogens or antigens. This proliferation suddenly multiplies the energetic and metabolic demands of the activated cell, and accordingly, accurate nutrient signalling is key to successfully accomplish the energetically onerous rounds of growth and division. Recently, components of the Rag GTPase pathway, a key nutrient signalling pathway that enables the anabolic capacity of the cell for rapid proliferation, were found mutated in follicular lymphoma (FL), an incurable B lymphocyte tumour. We have generated novel strains of mice that express these mutations, explored their oncogenicity and studied the reasons for such oncogenicity. We found that these mutations both suppress cell death and enhance proliferation, leading to hyperactive B cell responses upon immunisation and accelerated lymphomagenesis (FIGURE). Our results open up a potential therapeutic avenue for FL.

Chronic signalling of elevated nutrients mimics a diabetic state

Does an excess in nutrient intake correlate with human disease states because of caloric value, or because of the signalling cascades and cellular responses that overabundant nutrients activate? We sought to answer this question with genetically engineered mice to have a constitutively active nutrient-sensing cascade, but normal food intake. These mice express a modified form of the RagA GTPase (RagAGTP) that activates the mechanistic target of rapamycin complex 1, the pathway responsible for the synthesis of most anabolic reactions (proteins, lipids and nucleotides). The sole activation of this nutrient-signalling cascade drove elevated glucose levels in circulation, caused glucose intolerance and elevated the HOMA-IR, a parameter used to diagnose insulin resistance in patients. We are currently in the process of dissecting the contribution of each organ in these metabolic perturbations.