de la Roche Group

Hedgehog pathway activation in space and time

In order to understand Hedgehog signalling niches in vivo, we are analysing the expression of Hedgehog components and the activation of the pathway using cutting edge spatial multiplex technologies, such as HiPlex RNAscope, in complex lymphoid structures and other tissues at steady state and during infection and cancer. In addition, we created inducible Hedgehog reporter mouse models that will reveal activation kinetics in situ. 

Functional relevance of Hedgehog signalling in the cells of the immune system

We have developed bespoke conditional and inducible knockout and gain–of–function mouse models as well as specific reagents, such as antibodies to the main signalling components, to allow us to investigate the Hedgehog signalling pathway both during lymphocyte development and in mature peripheral immune cells. 

Mechanisms of immune Hedgehog signalling

We are using molecular biology techniques, microscopy and nanobody technology to determine how the Hedgehog signalling pathway is controlled and functions. We aim to uncover the signalling mechanics at immune synapses, the transduction of the signal to the cytoplasm and the nucleus as well as the unique make up of Hedgehog transcriptional complexes and the target gene signature in immune cells. 

Clinical Research Study “Research into Altered Lymphocyte Function in Health and Disease”

The laboratory is running a Clinical Research Study at Addenbrooke’s hospital. Here, we recruit rare patients with gain-of-function mutations in the Hedgehog pathway and cancer patients ‘on’ and ‘off’ treatment with the Hedgehog inhibitor Vismodegib. 

Developing novel immunotherapies against solid cancers

We have developed a novel immunotherapeutic portfolio against the cancer marker LGR5, which includes Chimeric Antigen Receptor (CAR) T and NK cells, bispecific engagers and antibody drug conjugates (ADCs). LGR5 is highly expressed in colorectal cancer and hepatocellular carcinoma – both cancers with unmed clinical need. Expression of LGR5 in healthy tissues is low or undetectable. We have demonstrated pre-clinical efficacy of our immunotherapeutics in murine models of human disease and are currently working on translating these towards the clinic. 

Other solid cancer targets are under investigation.