The role of extra centrosomes on the tumour microenvironment
The centrosome, an organelle important for cell division, is frequently amplified in cancer, including breast cancer. In this fellowship I propose to investigate how cells with centrosome amplification change the tumour microenvironment (TME) to promote breast cancer development. Recent work has shown that having extra centrosomes drive tumour growth in vivo, indicating that centrosome amplification is not a bystander of cancer, but promotes tumorigenesis. Consistent with a direct role in cancer, we previously demonstrated that centrosome amplification leads to chromosome instability and cell invasion. In addition to the cell autonomous effects of centrosome amplification, our lab has recently found that cells containing extra centrosomes also have non-cell autonomous effects via secretion of proteins that induce a paracrine invasive phenotype in mammary organoids. We also found that cells with pancreatic cancer cells with extra centrosomes secrete small extracellular vesicles (sEVs) that induce activation of the fibroblast-like pancreatic stellate cells (PSCs). Moreover, using xenograft immunocompetent mouse models, we found that induction of centrosome amplification in SUM225 human breast cancer cells leads to a strong innate immune infiltration (e.g. macrophages and neutrophils) surrounding the tumours. Guided by our preliminary data we hypothesise that altered secretion in cells with centrosome amplification changes the TME. Currently there is no published link between centrosome amplification and TME. I aim to characterise TME changes induced by centrosome amplification in vivo and to identify factors secreted by cells with extra centrosomes responsible for such changes. This work will be the first in-depth characterisation of TME in tumours containing extra centrosomes. Importantly, this project will start an exciting and novel research avenue bridging the centrosome and the TME fields.