Centre for Cell Signalling
Our aim is to understand how cells interpret and respond to extracellular cues, including drugs, in the normal and diseased state. The focus of our studies is on signal transduction by protein and lipid kinases, in particular PI 3-kinases (PI3Ks). Our work is divided between two research groups, the Cell Signalling Group and the Analytical Cell Signalling Group. See the 'Research Groups' tab below for further details.
Please click here for profiles of staff in the Centre for Cell Signalling.
Follow the links below to get a sense of what life is like for researchers in our centre:
- Advanced genetic mouse models that mimic pharmacological intervention. This Centre has created the largest collection of PI3K mutant mice world-wide. The majority of these mouse strains are available for research and for licencing through the Ludwig Institute for Cancer Research.
- Mass Spectrometry (shared with the ECMC) including LTQ-Orbritrap XL, Q-TOF Premier and TSQ Vantage and advanced separation technology (nanoflow UPLC).
- Unique computational tools for the analysis of mass spectrometry data.
The Cell Signalling Group
This group, led by Bart Vanhaesebroeck, focuses on the study of Phosphoinositide 3-kinases (PI3Ks). Uncontrolled PI3K signalling is one of the most commonly deregulated signalling pathways in cancer. PI3Ks also play roles in inflammation, allergy and metabolism, and the development of drugs that block PI3K action is actively pursued by the pharmaceutical industry.
Our group discovered the p110delta isoform of PI3K, and our seminal biological work in this area is now being translated to drug development. Clinical trials with p110delta inhibitors in oncology and allergy are in progress.
Our long-term aim is to delineate the roles of all PI3K isoforms in biology and signalling, and to uncover their potential utility as drug targets. Our key approaches include mouse gene targeting, cell biology and mass spectrometry, the latter using proteomic techniques described below.
The Analytical Cell Signalling Group
This group, led by Pedro Cutillas, has developed innovative technology to interrogate signalling pathways in a global fashion. This technology is now being used by the Analytical Signalling group and other groups at the Barts Cancer Institute to study signalling in cancer and has also been licensed to Activiomics Ltd, a spin-out company from the Barts Cancer Institute. The aim of this group is now to use these techniques in combination with molecular biology approaches to understand cancer heterogeneity at the molecular level through the application of a systems biology approach to cell signalling research.
Experimentally, the Analytical Cell Signalling Group integrates state-of-the-art mass spectrometry, advanced separation technology, cell biology and biochemistry to study cell signalling pathways in health and disease. The ultimate goal of this work is to contribute to the understanding of the fundamentals of cell signalling and to translate this knowledge to the design of personalised therapies to treat conditions with deregulated cell signalling pathways.
Analytical Cell Signalling
Pedro Cutillas developed mass spectrometry-based techniques for the quantification of signalling and innovative algorithms for the analysis of mass spectrometry data. These unique tools are currently being used to provide novel insights into the molecular biology of cancer and constitute the core technological platform of Actviomics, a spin-out company from Barts Cancer Institute.
- Our pioneering work on the identification and characterisation of p110delta identified this isoform of PI3K as a new drug target in immunity, allergy and cancer.
- In a collaboration with the Ludwig Institute for Cancer Research, a p110delta inhibitor development programme was incorporated into PIramed, which was purchased by Roche in 2008.
These p110delta inhibitors are currently under further development at Genentech/Roche. p110delta drug development programmes are ongoing in many pharma and biotech companies. p110delta inhibitors entered clinical trials in 2009, with very promising results in certain haematological malignancies, such as CLL (see examples here and here.) http://www.gilead.com/pr_1690087
Targeting p110delta has been the most successful clinical PI3K inhibitor development effort thus far.
- Bart Vanhaesebroeck cloned the p110delta isoform of PI3K (PNAS 1997:94:4330) and revealed p110delta-selective functions in leukocytes (Nature Cell Biol 1999:1:69) and cancer cells (Cancer Res 2003:63:1667). Our studies in mice revealed key functions for p110delta PI3K in adaptive immunity (Science 2002:297:1031), allergy (Nature 2004:431:1007) and leukaemia (Oncogene 2006:25:6648, Cancer Res 2009:69:1027).
- Together with his colleagues, Bart Vanhaesebroeck proposed the now universally accepted classification and nomenclature of the PI3K isoforms (Philos Trans R Soc Lond 1996:351:217; Trends Biochem Sci. 1997:22:267).
- Our team pioneered the use of so-called 'kinase knockin' mice in which the active site carries a mutation in a conserved ATP-binding amino acid residue, leading to inactivation of the kinase. To the best of our knowledge, the p110delta PI3K was the first kinase ever subjected to this type of genetic inactivation in the mouse. This kinase knockin strategy provides a more adequate physiological model for the effects of small molecule kinase inhibitors than classical gene knockout approaches (reviewed by us in Cell 2004:118:274; Trends Biochem Sci. 2005:30:194).
- Application of the mouse knockin strategy has allowed us to uncover the first physiological roles of the p110alpha (Nature 2006:441:366; Nature 2008;29:453) and p110beta (PNAS 2008;105:8292) isoforms of PI3K.
- We have reviewed the PI3K field on numerous occasions (see amongst others: Nat Rev Moll Cell Biol. 2012: in press - Nat Rev Mol Cell Biol. 2010:11:329 - Trends Biochem Sci. 2009:34:115 - Trends Immunol. 2007:28:80 - Trends Biochem Sci. 2005:30:194 - Nat Rev Immunol. 2003:3:317 - Annu Rev Biochem. 2001:70:535 - Biochem J. 2000:346:561 - Trends Biochem Sci. 1997:22:267).
We are extremely proud that half of the former postdoctoral fellows from our Centre for Cell Signalling now run their own research teams, in academia or industry. See:
- Klaus Okkenhaug
- Mariona Graupera
- Julie Guillermet-Guibert
- Lazaros Foukas
- Evangelia (Litsa) Papakonstanti
- Gemma Nock Research Analyst at Decision Resources
- Geraldine Farjot (Sanofi-aventis)
- Clotilde Billottet