Using single transcriptomic and genetic manipulation to investigate the cellular interaction in preneoplastic cell development niche

Oncogenic mutations are required for tumourigenesis, but not all oncogene expressing cells will go on to develop into cancer. The majority of oncogene expressing preneoplastic cells (PNCs) fail to develop into malignant tumours. This process is highly regulated by non-cancer cells within the surrounding niche to aid the growth and survival of preneoplastic cells.

Neutrophils have been identified as playing a tumour-promoting role during tumour initiation, influencing tumour progression. While evidence suggests that blocking inflammation reduces cancer incidence, a better understanding of the precise timing and nature of immune cell responses in early stages of cancer development is needed for designing chemopreventative strategies.

My PhD project sets out to investigate the interactions between neutrophils and PNCs using a combination of zebrafish in vivo models and single cell RNA-sequencing data analysis. The aim is to dissect neutrophil heterogeneity and explore cell-cell communication pathways involved in neutrophil-PNC interactions. A key focus of my project is to investigate neutrophil maturation within the PNC niche.

Current preliminary data suggests that neutrophils in PNC-bearing zebrafish larvae undergo an accelerated development turn-over and emigrate from hematopoietic tissue pre-maturely. In vivo live imaging analysis revealed that immature neutrophils form more transient interactions with PNCs and are in more contact with PNCs than mature neutrophils. Using CRISPR/CAS9 approach to deplete neutrophils leads to reduced PNC proliferation.

These findings suggest that neutrophils promote PNC growth in the zebrafish skin PNC model that I will be working with, and that neutrophils at different maturation stages might play different roles in impacting PNC progression.