The role of extramedullary granulopoiesis in pancreatic cancer progression and spread
Dr Leo Carlin & Prof Jen Morton
Labs: Leukocyte Dynamics & Preclinical Pancreatic Cancer
Duration: 4 years, flexible start date up to October 2025
Closing Date: Monday 25 November 2024
Interviews for this position will take place January/February 2025
Background
Neutrophils are essential immune cells for anti-microbial defence and neutrophil defects leave the host critically immunocompromised. However, recent work has revealed that these leukocytes also play important roles in cancer with both potent anti- and pro-tumour activity1, 2. Neutrophils have been found to be potently pro-metastatic in models of colorectal, breast, and most relevant to this project, pancreatic cancer3, 4, 5, 6.
Recent work has established that there is a much higher degree of heterogeneity in neutrophil phenotype than was previously appreciated7, 8, 9. This plasticity is surprising on one level due to the relatively short life of the cells, but on another level, we now understand both heterogeneity in ontogeny and environment-driven plasticity to be a key feature of other myeloid cells.
Neutrophil heterogeneity can be both regulated at a systemic level and local level, due to changes in neutrophil production (e.g. “emergency granulopoiesis”) and tissue imprinting10. Our own work has uncovered features consistent with extramedullary granulopoiesis within liver tumours11 as well as highlighting the spleen as a relevant extramedullary production site in cancer capable of producing neutrophils distinct from those that originate in the bone marrow9.
Research Question
This project will build on previous work in our labs6, 9 and others, and use sophisticated, disease positioned mouse models to interrogate the role of neutrophils produced outside of the bone marrow in pancreatic cancer progression and metastasis.
Skills/Techniques that will be gained
The project will use advanced techniques to:
- Elucidate the localisation and identity of neutrophil phenotypes in pancreatic cancers, the spleens of tumour bearing mice, and metastases using scRNAseq, spatial transcriptomics and multiplexed immunofluorescence in gold-standard autochthonous spontaneously metastatic mouse models of pancreatic cancer exploiting a wealth of archived tissue spanning multiple organs and stages of disease.
- Use multiplexed live tissue imaging and intravital microscopy to monitor neutrophil behaviour and cell: cell interactions directly focusing in on particular sites and timepoints.
- Exploit high parameter spectral flow cytometry to understand temporal shifts in neutrophil phenotype during the progression of cancer.
For questions regarding the application process, PhD programme/studentships at the CRUK Scotland Institute or any other queries, please contact phdstudentships@beatson.gla.ac.uk.
Closing date: Monday 25 November 2024
Applications are open to all individuals irrespective of nationality or country of residence.
Relevant Publications
