Understanding the origin and the function of metabolic reprogramming in cancer associated neutrophils within the metastatic niche

Primary Supervisor: Dr Luigi Ombrato, Barts Cancer Institute, QMUL

Secondary Supervisor: Dr Mariia Yuneva, The Francis Crick Institute

Tertiary Supervisor: Prof Kairbaan Hodivala-Dilke, Barts Cancer Institute, QMUL

Introduction

Neutrophils are the most abundant circulating leukocytes in humans and they have long been known as an essential component of the innate immune system involved in infective processes and autoimmune diseases. Neutrophils’ role in cancer has only been recently appreciated and novel neutrophil functions in cancer have been identified in the last decade, acknowledging them as a relevant component in the tumour microenvironment (TME) [3]. Importantly, high neutrophil infiltration has been associated with poor prognosis in most human cancers, in line with their tumour-supportive role shown in mouse models. Indeed, neutrophils can also play an anti-tumorigenic role suggesting an emerging level of plasticity within these cells[3.] Metabolic reprogramming is a hallmark of cancer[4] and immunometabolism is rapidly becoming a key research area. While metabolic changes have been largely characterised in macrophages and Tcells within the TME[5] very little is known about cancer associated neutrophil metabolism. Particularly in metastasis these changes are difficult to study. Among the underlying reasons is the technical barrier to identify and isolate TME cells specifically from metastatic niches and to preserve their metabolism during the isolation process.

Hypothesis

Cancer associated neutrophils change their metabolic features in metastasis to support cancer cell growth.

Supporting preliminary data

By establishing an innovative technology that allows cancer cells to directly label their neighbouring cells in the niche, we have specifically isolated neutrophils from lung metastases in a breast cancer mouse model and performed proteomic analysis[1]. When comparing the niche neutrophils with the neutrophils from the same lung but distant from the metastatic foci, we observed that they upregulate proteins associated with oxidative phosphorylation. This finding was in line with higher levels of intracellular reactive oxygen species (ROS) detected in niche neutrophils[1]. Next, we set-up a 3Dscaffold co-culture system where we plated primary lung neutrophils and breast cancer cells and we demonstrated that ROS is required for a neutrophil-dependent tumour supportive function1. The trigger of this metabolic change in neutrophils within the metastatic microenvironment and how the cancer cells benefit from this increase in ROS remains unknown.

The aim of this project will be to a)characterise the metabolic interactions within the metastatic niche by specifically focusing on neutrophils, b) identify the source of neutrophil metabolic “reprogramming” and c) study how these changes impact on cancer cell growth.

The student will implement the 3D co-culture system previously used1 to more closely mimic the TME complexity ex vivo by also including macrophages and fibroblasts that are largely represented in the early metastatic niche1. Metabolic pathways will be subsequently modulated in the co-culture to identify strategies to impair cancer cell proliferation. The findings generated will be corroborated by using in vivo metastatic mouse models.

Immunometabolism is an emerging research field which holds great potential to extend future therapeutic options in cancer patients. However, this area is still poorly studied in cancer. The knowledge generated from this project will expand our understanding in the field and will ultimately lead to identify molecular targets to impair metastatic growth in breast cancer.

A graduate with a strong interest in cancer cell biology/metabolism/immune-oncology, with or is expecting at least an upper second class honours degree in a relevant biological/biochemical subject, is required for this project. An MSc/MRes, or laboratory experience, in a relevant area may well prove advantageous.

Potential research placements

1. Training in the isolation of primary cells from murine tissues and breast tumours, and characterisation of these cells using flow cytometry and imaging. Dr Luigi Ombrato, BCI.

2. Metabolomics sample and data analysis. Dr Mariia Yuneva, The Francis Crick Institute

3. Optimisation of culture conditions to study cell-cell interactions in vitro and analysis of 2D and 3D co-cultures. Dr Adrian Biddle, Blizard Institute, QMUL

The funding for this studentship covers students with home tuition fee status only. For more information on home tuition fee status please visit the UKCISA website. Please note that we will only be able to offer studentships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).

References

1. Ombrato, L. et al., Metastatic-niche labelling reveals parenchymal cells with stem features. Nature, 572:603-608. doi: 10.1038/s41586-019-1487-6. (2019)

2. Méndez-Lucas, A. et al., Identifying strategies to target the metabolic flexibility of tumours. Nature Metabolism 2:335-350. doi: 10.1038/s42255-020-0195-8. (2020)

3. Jaillon, S. et al., Neutrophil diversity and plasticity in tumour progression and therapy. Nature Reviews Cancer. Sep;20(9):485-503. doi: 10.1038/s41568-020-0281-y. (2020)

4. Vander Heiden M.G. and DeBerardinis, R.J. Understanding the intersection between metabolism and cancer biology. Cell; 168:657-669. doi: 10.1016/j.cell.2016.12.039. (2017)

5. Li, F. and Simon, M.C. Cancer cells don’t live alone: metabolic communication within tumor microenvironments. Developmental Cell 54:183-195 doi: 10.1016/j.devcel.2020.06.018. (2020)

For informal enquiries relating to the project please contact Dr Luigi Ombrato: l.ombrato@qmul.ac.uk

For general enquiries regarding the CRUK CoL Centre training programme please contact Annabelle Scott: annabelle.scott@ucl.ac.uk