Bass Hassan

Structure and Function of Cancer Genes

Identifying and validating functional genomic co-dependencies to improve precision of cancer treatment.

Multiple genes simultaneously regulate growth, survival and the propensity for cancer cells to disseminate to other body sites.  We are currently focused on the functional mechanisms that co-ordinate these phenotypes in cancers of bone and soft tissues (sarcomas).  Ultimately, our aim is to identify and validate functional co-dependencies and to evolve the experimental basis of co-targeting strategies that improve precision (personalisation) of treatment.

Our previous work mainly concerned gene dosage interactions between two reciprocally imprinted genes (mono-allelic expression) that are disrupted in cancers.  The genes for the growth promoting Insulin-like growth factor 2 ligand and its negative regulator, the IGF2/ Mannose 6-phosphate receptor (IGF2R) are reciprocally imprinted (parent of origin dependent allelic silencing).  The relative dosage of both genes is critical for normal mammalian development and is the reason for mammalian sexual reproduction.  We showed that in murine cancer models disruption of IGF2 supply (both loss of imprinting and mutation of IGF2R) results in tumour progression.  IGF2R negatively regulates IGF2 by binding with high affinity and selectivity.  Following structural determination of the IGF2 binding domain, we discovered that IGF2R domain 11 evolved prior to genomic imprinting in monotremes.  Directed evolution then led to the generation of Fc-domain 11 mutated versions that act as specific and high affinity soluble ligand traps for IGF2, reversing IGF2 induced hypoglycaemia in vivo (IGF2-TRAP).   IGF2-TRAP is the basis of a novel human therapeutic that can reverse excess IGF2 in tumour associated hypoglycaemia syndrome and where IGF2 acts as a resistance mechanism to single target signalling blockade.

Our current work is focused towards sarcomas, at least 80 different and complex cancers derived from mesenchyme. Through investigation of functional co-dependencies of oncogenic gain of function and tumour suppressor loss of function, we aim to define the contexts for both lethality and the immune recognition of cancer as non-self.  Exploiting cancer specific functional vulnerabilities is a pre-requisite for effective personalisation of cancer therapy.  For example, using functional screens in human sarcoma cell lines based on whole genome CRISPR/Cas12a dual sgRNA libraries, we have validated novel dependent mechanisms to a receptor tyrosine kinase inhibitor identified in a human clinical study in Ewing sarcoma (expressing EWS-FLI1 fusion genes).  Further investigation of genomic based co-dependencies such as synthetic lethality is ongoing in a variety of sarcoma subtypes.  Moreover, we have utilised a genome wide discovery pipeline in Ewing sarcoma, Rhabdomyosarcoma and MPNST to select for somatic genomic target MHC presentation and immune T-cell based selection.   This work is integrated with our translational Oxford Precision Oncology for Sarcoma (OxPOS) programme.

Group members

  • Bass Hassan (Group leader)
  • Rachael Wilkinson (Postdoc)
  • Richard Wallbank (Postdoc)
  • Mirvat Surakhy (Postdoc)
  • Tanya Ren (Graduate student)
  • Qinan Qian (Graduate student)
  • Paul Metz (Graduate student)
  • Hannah Mallon (Graduate student)
  • Isabel Karia (Graduate student)
  • Stuart Brown (Postdoc)
  • Lara Bonney (Graduate student)
  • Sofia Alves-Vasconcelos (Graduate student)

Selected Publications

Available student projects