Rise of the Structure-encoded UNC5 interactome in aggressive behaviours of Neuro-developmental tumours

Paediatric tumours represent a challenge in the landscape of cancer research.

Unlike adult cancers, they typically originate from embryonic cells, from which they inherit characteristic embryonic features. This is exemplified by neuroblastoma (NB), the most common solid tumour in young children. NB is a heterogeneous cancer with aggressive metastatic forms, which emerges from neural crest cells.

These cells normally undergo a complex migratory process that depends on the functions of cell surface signalling receptors.

In a recent, ground-breaking study we found that NB cells co-opt one specific family of these receptors (UNC5) and the ligand GPC3 to disseminate (Cell 2022).

Disruption of this interaction in vivo impacted on cell cohesion, migratory properties and redirected tumour localisation.

Here we provide unpublished data analysis, suggesting that an entire UNC5 interaction network, involving multiple different ligands besides GPC3, is at play in malignant NB.

Understanding the mechanisms driving NB cell aggressive behaviours requires investigation of this network in the embryonic context. A key strength of the proposal is our unique approach bringing molecular/structural biology to in vivo experiments.

Our strategy maximises the use of targeted, structure-based perturbation experiments, where we control the activity of individual receptor interaction precisely, in vivo.

We also have the necessary access to patient samples and will use our innovative avian xenograft model which recapitulates the embryonic environment of NB.

In a final workpackage we will apply our strategy, developed with a focus on NB, to two other paediatric cancers where UNC5 is expressed.

In sum, the results of SUNRISE will produce a first detailed picture of the where, when and how UNC5 network interactions drive paediatric cancer biology, and could lead to new therapeutics, for example, using nanobody technology.