Using a zebrafish tumour initiation model, single cell transcriptomics and in vivo live imaging to dissect mechanisms driving the development of tumour promoting neutrophils from the inception of cancer.

Students will be registered for their degree at either the University of Glasgow or Edinburgh, depending on the project they apply for. This scheme is open to both UK and international applicants.

https://www.crukscotlandcentre.ac.uk/training/phd-studentships

The aim of this project is to establish the mechanisms that drive the establishment of tumour promoting neutrophil phenotype during tumour initiation, and to identify targets for reversing this tumour promoting neutrophil phenotype.

Tumourigenesis is initiated by a single cell acquiring an oncogenic mutation, which drives preneoplastic cell (PNC) development. Although it is accepted that oncogenic mutations are required for tumourigenesis, these are not sufficient. Due to lack of accessible models to study the earliest stages of preneoplastic cell development, little is known as to how oncogene expressing PNCs interact with host cells within their developing niche; and how a permissive niche is established that allows tumour development. A better understanding of the mechanisms that favour PNC progression toward tumourigenesis could provide novel targets for cancer early detection and prevention. Tumour associated neutrophils have been shown to play a role in promoting tumour growth, facilitate metastasis and reduce the efficacy of cancer immunotherapy. It is well documented that aberrant neutrophils are detected in circulation in cancer patients, and this can be a prognostic marker for patient response to therapy. However, it is not clear how a growing tumour and the host innate immune system co-evolve in such a way that tumours hijack the host innate immune system to promote their growth. And we only have limited approaches to re-educate the host innate immune system for tumour elimination and to enhance cancer immunotherapy.

Using a zebrafish model of hRASG12V driven skin PNC development that we developed, we found a rapid recruitment and activation of neutrophils toward a tumour promoting phenotype at the inception of PNC development. In vivo live imaging analysis revealed a systematic response of host neutrophils upon PNC induction. There is an accelerated neutrophil death, premature emigration from caudal hematopoietic tissue, enhanced neutrophil proliferation and altered response to an acute wound. Our scRNAseq data of PNC and associated neutrophils revealed that neutrophils in our PNC model switched to a pro-tumour phenotype at the inception and we have identified candidate mechanisms that might mediate the systemic neutrophil phenotype changes as well as PNC vs neutrophil crosstalk.

In the current project, we will be using integrated analysis to re-examine neutrophil scRNAseq data from our PNC model together with scRNAseq datasets available from mammalian systems to identify conserved mechanism that might drive the establishment of a tumour promoting neutrophil phenotype. We will harness powerful zebrafish genetics with an in vivo live imaging approach to examine the function of candidate pathways in altering neutrophil development and phenotype in our PNC model. We will evaluate how PNC progression might be altered when we manipulate neutrophil phenotype or alter PNC-neutrophil cross talk. 

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