Cell Signalling (Oncology)

Overview

We study signal transduction in cells. We focus on the PI3K signalling molecules which are overactive in cancer, some immune contexts and in overgrowth syndromes. We aim to understand PI3K action and exploit this knowledge for therapy. Over the years, our studies have contributed to PI3K drug development, clinical trials and drug approval.

A highlight of our work to date is the discovery of PI3Kdelta, a PI3K family member that is highly expressed in white blood cells. PI3Kdelta inhibitors are now approved for some B-cell malignancies and are being tested in cancer immunotherapy, including in melanoma and lung cancer.

After a long focus of inhibiting PI3Ks, we are now developing compounds to activate PI3K, the first study on which was published recently (rdcu.be/dcUpi). This work is in collaboration with Roger Williams at the MRC-LMB in Cambridge and AstraZeneca Open Innovation. In preclinical studies, these compounds can protect cardiac and neural tissue from the sort of damage seen in heart attack and stroke, and also stimulate nerve regeneration after injury. Paradoxically, such compounds may also be useful in cancer, by over-activating cell signalling.

Research

Our laboratory covers three main lines of research.

1. PI3K isoform function

We aim to uncover the functions of the PI3K family members in normal physiology and in disease, and to understand their molecular mechanism of action.

Sponsors: Cancer Research UK, EU, UKRI

2. PTEN Hamartoma Tumour Syndrome (PHTS)

this is a human condition in which the PTEN tumour suppressor gene is faulty, predisposing to overgrowth, autism-like spectrum and cancer. PTEN is an enzyme which keeps PI3K in check. We aim to understand how PTEN works in an organism, and to explore if PI3K inhibitors can be used to alleviate PHTS.

Sponsors: PTEN Research Foundation

3. Development of PI3K activators

Situations exist in which it would be useful to have PI3K activators. Examples are wound healing, nerve regeneration, stroke and cardioprotection, conditions in which PI3K is known to transmit regenerative and protective signals into the cells. PI3K activators could also be used to boost the immune response, and to stimulate cells in the brain to repair neuro-degenerative damage. Paradoxically, cells with too much PI3K, such as cancer cells, can also be destroyed by PI3K overactivation ('too much of a good thing').

Talks: For a general introduction to PI 3-kinase and lipid messengers: hstalks.com/bs/461/.

Hear from our group

Recent publications

1. Madsen RR, Le Marois A, Mruk ON ... Vanhaesebroeck B. Oncogenic PIK3CA corrupts growth factor signaling specificity. Mol Syst Biol. 2025 Feb;21(2): 126-157.
2. Courreges CJF, Davenport ECM, Bilanges B ... Vanhaesebroeck B, Okkenhaug K. Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development. Front Immunol. 2024 Nov 27;15:1374621.
3. Herms A, Colom B, Piedrafita G ... Vanhaesebroeck B, Jones PH. Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus. Nat Genet. 2024 Oct;56(10): 2144-2157.
4. Thowfeequ S, Fiorentino J, Hu D ... Vanhaesebroeck B, et al. An integrated approach identifies the molecular underpinnings of murine anterior visceral endoderm migration. Dev Cell. 2024 Sep 9;59(17): 2347-2363.e9.
5. Conduit SE, Pearce W, Bhamra A ... Vanhaesebroeck B. A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease. Nat Commun. 2024 Aug 21;15(1): 7181.
6. Gong GQ, Vanhaesebroeck B. Precision Targeting of Mutant PI3Kα. Cancer Discov. 2024 Feb 8;14(2): 204-207.
7. Kobialka P, Llena J, Deleyto-Seldas N ... Vanhaesebroeck B, Efeyan A, Graupera M. PI3K-C2β limits mTORC1 signaling and angiogenic growth. Sci Signal. 2023 Nov 28;16(813): eadg1913.
8. Han H, Yang Y, Jiao Y, Qi H ... Vanhaesebroeck B, et al. Leverage of nuclease-deficient CasX for preventing pathological angiogenesis. Mol Ther Nucleic Acids. 2023 Aug 6;33: 738-748.