Impact of neural signalling in cancer pain and clinical outcomes

Our aim is to determine how human cancers remodel their neural microenvironment and how resulting neuronal states influence tumour cell plasticity, antitumour immunity and disease progression. We will identify tumour- and microenvironment-derived signals driving neuronal remodelling, characterise the functional and spatial heterogeneity of cancer–neuron interactions, and determine how fibroblasts and extracellular matrix organisation shape tumour-associated neural niches.

We propose (1) to functionally validate cancer-neuron signalling pathways already identified by our group, (2) discover and characterise additional molecular and cellular mechanisms underlying neuronal remodelling and perineural invasion, and (3) to pharmacologically manipulate pathways identified in (1) and (2) to alleviate pain and/or alter disease outcome.

Specific aims and work packages will be refined according to the complementary expertise of collaborating partners.

The project will integrate several complementary models, including in vitro coculture (including microfluidics), functional genomics (CRISPR to manipulate identified targets, cellular barcoding to characterise heterogeneity), human tissue characterisation (genomics, including spatial transcriptomics) and in vivo orthotopic graft models for functional and therapeutic validation.

We are looking for partners with any of the following skills and expertise:

• Neuronal circuit manipulation: chemogenetic/optogenetic approaches and selective activation, inhibition or ablation of defined neuronal populations, particularly in vivo.

• Neuroanatomy and quantitative innervation mapping: 3D nerve reconstruction, axonal tracing and quantitative assessment of tumour-associated neural remodelling.

• Computational and systems biology, cellular networks

• Generation/integration of multi-omics data

• Tumour microenvironment models (including spatial proteomics)

• Microfluidics

• Whole organ imaging (e.g. pancreas, liver…)

• Modellisation/virtual twins

• Cell-cell and cell-matrix communications

• Other cancer models with neural signalling

• Cancer immunology

We welcome industry partners for target validation and preclinical drug evaluation and are also interested in contributing our models and expertise to projects coordinated by others. Where appropriate, health-economic expertise could evaluate the economic benefit of interventions targeting cancer-associated pain and disease outcomes.

Our project currently focuses on pancreatic cancer, with priorities informed by people with lived experience of this disease, but we seek collaborations to extend this framework to other cancers characterised by substantial pain, poor prognosis and neural interactions, including head and neck, gastric, mesothelioma or other cancers. This comparative approach will extend the reach of our findings and discriminate tumour-specific from holistic mechanisms of cancer–neuron communication.