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Cancer Cell Biology Programme

Growth Factors, Nutrients and Cancer Group

Group Leader:  Nabil Djouder
Research highlights

We have a particular interest in studying gastrointestinal track disorders. Our work in this area focuses on metabolic organs such as the liver, intestine and pancreas, as these 3 organs are physiologically interconnected and influenced through their exocrine and/or endocrine functions and microbiota (FIGURE). Our task is thus to generate new mouse models mimicking human disease and to study mechanisms and events iniating disease development. We also use patient-derived xenograft models and organoids to translate our findings into clinical perspectives. Guided by experimental mouse models combined with the use of human data, we aim to provide a comprehensive study for a rational approach towards the development of novel mechanism-based therapeutics to prevent, ameliorate and treat diseases.

Identifying new components of growth factor and nutrient signalling cascades

We identified 2 components of the growth factor and nutrient signalling cascades regulating the mTORC1 pathway: Uncoventional prefoldin RPB5 interactor (URI) (Djouder et al., 2007) and Microspherule protein 1 (MCRS1) (Fawal et al., 2015).

Uncoventional prefoldin RPB5 interactor (URI): URI is member of the R2TP/URI-prefoldin like complex, which contains not only prefoldin subunits but also RNA polymerase binding subunit (RPB5), ATPases/helicases RuvB-like protein 2 (RUVBL2, also known as 48- kDa TATA box-binding proteininteracting [TIP48] or reptin) and RuvB-like protein 1 (RUVBL1, also known as 49-kDa TATA box-binding protein- interacting [TIP49] or pontin) and co-chaperones such as heat shock protein 90 (HSP90). URI is a downstream component of the growth factor and nutrient signalling pathways. It is phosphorylated by S6K1 and has an oncogenic role in ovarian cancer and HCC development.

Microspherule protein 1 (MCRS1): MCRS1, in an amino aciddependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 depletion promotes Rheb/ TSC2 interaction, rendering Rheb inactive and delocalising it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation.

Generation of genetically engineered mouse models
  • 2 conditional knock-outs (URI and MCRS1 loss-of-function).
  • 3 knock-ins (over-expression of URI (wt), URI (S371A) and MCRS1).
Research achievements
  • Inflammatory cues and nutrient overloads up-regulate hepatic URI.
  • URI is an oncogene initiating NASH and HCC.
  • Nicotinamide riboside to prevent liver and pancreas cancers.
  • MCRS1 activates mTORC1 in response to amino acids.
  • URI is the first identified OGT regulator in response to glucose fluctuations.
  • Glucose depletion can induce oncogenic signals through OGT/c-MYC regulation.
  • c-MYC is oncogenic and tumour suppressive depending on nutrient availability.