Dr Yi Feng, Dr Ava Khamseh, Dr Leo Carlin, Dr Xiao Fu
Project Description
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.
Training offered
scRNAseq data analysis; transgenic zebrafish tumour initiation models; zebrafish genetics; CRISPR/CAS9 gene editing in zebrafish models; in vivo live imaging; Imaging analysis (potentially machine learning approach for image analysis); various staining procedures for zebrafish larvae
For further information on the project or informal enquiries, please contact Dr Yi Feng, This email address is being protected from spambots. You need JavaScript enabled to view it.
To place an application, please visit this site at the University of Edinburgh: https://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&edition=2022&id=237
When submitting your application please upload the completed recruitment form.
Lab Websites
Dr Yi Feng
Dr Ava Khamseh
Dr Leo Carlin
Dr Xiao Fu
Papers of interest
1. Abigail M. Elliot, Isabel Ribeiro Bravo, Jeanette Astorga Johansson, Esme Hutton, Richard Cunningham, Henna Myllymäki, Kai Yee Chang, Mariana Beltran, Ross Dobie, Phil Elks, Carsten Gram Hansen, Neil Henderson, Yi Feng. Oncogenic RAS drives rapid onset cellular plasticity and elicits a tumour-promoting neutrophil response at the inception of preneoplastic development. bioRxiv 2023.11.10.566547; doi: https://doi.org/10.1101/2023.11.10.566547
2 Mackey JBG, McFarlane AJ, Jamieson T, Jackstadt R, Raffo-Iraolagoitia XL, Secklehner J, Cortes-Lavaud X, Fercoq F, Clarke W, Hedley A, Gilroy K, Lilla S, Vuononvirta J, Graham GJ, De Filippo K, Murphy DJ, Steele CW, Norman JC, Bird TG, Mann DA, Morton JP, Zanivan S, Sansom OJ, Carlin LM. Maturation, developmental site, and pathology dictate murine neutrophil function. bioRxiv. 2021. doi: https://doi.org/10.1101/2021.07.21.453108
3. van den Berg MCW, MacCarthy-Morrogh L, Carter D, Morris J, Ribeiro Bravo I, Feng Y, Martin P. Proteolytic and Opportunistic Breaching of the Basement Membrane Zone by Immune Cells during Tumor Initiation. Cell Rep. 2019 Jun 4;27(10):2837-2846.e4. doi: 10.1016/j.celrep.2019.05.029.
4. Antonio N, Bønnelykke-Behrndtz ML, Ward LC, Collin J, Christensen IJ, Steiniche T, Schmidt H, Feng Y, Martin P. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J. 2015 Sep 2;34(17):2219-36. doi: 10.15252/embj.201490147.
5. Feng Y, Renshaw S, Martin P. Live imaging of tumor initiation in zebrafish larvae reveals a trophic role for leukocyte-derived PGE₂. Curr Biol. 2012 Jul 10;22(13):1253-9. doi: 10.1016/j.cub.2012.05.010.