The role of metabolic alterations in neutrophils during breast cancer metastasis

Key information

Application close date
07 February 2023, 11:59 GMT
Hours per week
36 (full time)
Application guidance
Posted 22 December 2022

Research topics

Immunology Metabolism Stem Cells Tumour Biology
Background texture taken from the lab imagery.

This is a summer student position supervised by Nicolas Rabas from Ilaria Malanchi's lab

Introduction to the Science

We are interested in cancer and how the primary tumour induces changes in the host on a whole organism or systemic level. We have a particular focus on how the immune system responds to tumours and how this response promotes tumour progression and metastasis. In this project, we are focussing on the innate immune system and neutrophils -  short-lived immune cells that are are classically seen as “first responders” during pathogen infection when they are rapidly recruited to infected sites. Moreover, neutrophils have diverse roles in many aspects of physiology and, can play  both pro and anti-tumorigenic roles depending on the specific context.

During metastasis, systemic changes induced by the primary tumour can prime distal organs, altering the properties of the tissue to make them a more receptive site for disseminated cancer cells. In this way, primary tumours induce the formation of a pre-metastatic niche to promote metastasis. Tumours also induce both a drastic increase in neutrophil abundance and alterations in neutrophil phenotypes.

 

About the Project

Our lab, along with others, has previously identified a key role for neutrophils in priming a premetastatic niche in the lung, in breast cancer models with lung metastasis (see ref. 1).  Recently, we have uncovered a specific alteration in neutrophil metabolism that arises in multiple different diseases, including cancer, infection and systemic inflammation resulting from obesity. This altered metabolic state of neutrophils changes the profile of metabolites they release. We have shown that these neutrophil-derived metabolites promote aggressive characteristics of cancer cells being key aspects of their metastatic potential.

The student will work on key outstanding questions concerning the mechanism by which tumours induce this pro-metastatic metabolic state in neutrophils. We will begin with conditioned-media experiments using cancer cell lines and primary tumour cells in vivo and in vitro to identify the tumour-derived signals that drive the transcriptional changes in neutrophils responsible for their altered metabolic behaviour. In addition, we will identify the stage during neutrophil development when these metabolic alterations arise. This project will involve a combination of techniques including cell culture, flow cytometry, qPCR, immune histochemistry and Immunofluorescence microscopy, along with various image analysis techniques. Depending on progress, this may be extended to include preparation and analysis of bulk RNA sequencing data and metabolomics.

 

About You

This project would suit a candidate studying a biological/biomedical discipline, with an interest mammalian cells and an appreciation for both cellular biology and whole organism physiology.

 

References

1.         Wculek, S.K. and Malanchi, I. (2015)

            Neutrophils support lung colonization of metastasis-initiating breast cancer cells.

            Nature 528: 413-417. PubMed abstract

2.         Quail, D.F., Amulic, B., Aziz, M., Barnes, B.J., Eruslanov, E., Fridlender, Z.G., . . . Kubes, P. (2022)

            Neutrophil phenotypes and functions in cancer: A consensus statement.

            Journal of Experimental Medicine 219: e20220011. PubMed abstract