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Bass Hassan

Structure and function of genes that regulate tumour phenotypes

Structure and function of genes that regulate tumour phenotypes

Multiple cellular pathways are deregulated in tumours as a result of gene disruption, some of which alter growth and the propensity for tumour cells to invade and spread to other body sites.  The importance of an experimental understanding of the basic science that underpins our knowledge of tumour cell behaviour is the focus of our work in the group.  Our aim is to translate these findings where possible.

Genes that are reciprocally imprinted

Gene dosage is a hallmark of the function of imprinted genes and the basis for sexual reproduction in mammals.  Two reciprocally imprinted genes, the growth promoting IGF2 ligand and the negative regulator, the IGF2/ Mannose 6-phosphate receptor (IGF2R), are critical for normal mammalian development.  Gain of function of IGF2 and loss of function of IGF2R are two events that can also occur in cancer.  We have characterised IGF2 function in a number of murine models of tumour development, and our work indicates that IGF2 gain of function through either loss of imprinting or mutation of IGF2R, can act as a progression factor during the early stages of tumour formation. Thus targeting IGF2 may, in some instances, be beneficial to control the growth of tumours.    

With Professor Matt Crump, University of Bristol, we have also studied the structural basis of the co-evolution of binding of the IGF2 ligand to domain 11 of the IGF2R receptor with respect to imprinting of the respective genes. We have exploited this basic knowledge of the interaction to develop versions of domain 11 of IGF2R that can act as a soluble ligand trap for IGF2.  The development of IGF2-TRAP has led to discovery of novel mutants that regulate the kinetics of IGF2 binding, that have now been patented.  Further work of the high order interactions of IGF2R with mannose 6-phosphate also define the pH dependencies of the receptor and ligand binding.

As some human cancers over-express poorly processed forms of IGF2, such that the endocrine insulin-like actions manifest as tumour associated hypoglycaemia.  Use of a specific inhibitor of IGF2, such as an IGF2-TRAP developed by the group, is one way to mitigate the effects of excess IGF2 in patients.  Development of IGF2-TRAP requires further validation, protein production and a first in man clinical trial.

Genes that regulate the transition to carcinoma

Genes commonly disrupted in invasive carcinomas are functionally relevant, as this process is the cause of cancer mortality.   Genes that are associated with early stage tumours are important to understand initiation, as are those involved in late stage established cancers.  Targeting the pathways involved in the transition between these extremes, often referred to as an epithelial to mesenchymal transition (EMT), may be more effective for prevention through arresting the evolution of the carcinoma phenotype.  These genes include E-cadherin (Cdh1) and Smad4.  E-cadherin has two functions, one based on the intra-cellular binding of the Wnt mediated transcription factor, beta-catenin, and the other in forming cell adhesions through extra-cellular homophilic strand exchange.  We have shown that these two functions may act together in Cdh1 loss of function in mouse organoid models, and is the basis of both functions accounting for E-cadherin tumour suppressor function.  Investigation of the TGF beta pathway using Smad4 MH1 domain deletion, also identified dependent genes that account for EMT.  Identification of ID1 in an organoid model as a key regulatory gene further defined the Smad dependencies of the TGF/BMP ligand-receptor interactions and their translation to human cancer.

Genes that regulate tumours of mesenchyme

Novel genes and translocations are specific to a large group of rare tumours derived from mesenchyme, called sarcomas.  Our understanding of the function of these genes remains limited, partly because of a lack of genetic models.  The advent of CRISPR/Cas9 genome engineering has paved the way for functional genomics.  For example, we have been interested in translation of the IGF pathway dependency of some patients with Ewing sarcoma.  With the EuroSarc consortia, we completed a Phase IIa clinical trial of a dual IGF1/IR kinase inhibitor where we collected tissue before and after treatment.  We identified a gene expression signature associated with response to the agent.  Genetic complementation of CRISPR deleted target genes in cell lines, validated the mechanism based on neural differentiation via transcriptional repressor function.  These functional mechanisms extend the limited observational information obtained from clinical trials, and offer the basis for rationale designed treatment combinations in Ewing sarcoma resulting in synergistic lethality.

Further work aims to further evaluate the sarcoma genome with respect to evolution, synergistic targets and immune presentation, approaches that have relevance for more effective translation for patient benefit.

The team’s expertise depends on the ongoing projects, ranges from murine models, molecular and structural biology, computational biology through to early phase clinical trials. Our integrated and vibrant team spans bench to bedside, from basic to translational research.