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The role of extra centrosomes on the tumour microenvironment

Periodic Reporting for period 1 - CentrosoTME (The role of extra centrosomes on the tumour microenvironment)

Okres sprawozdawczy: 2019-06-01 do 2021-05-31

The centrosome, an organelle important for cell division, is frequently amplified in cancer, including breast cancer. In this fellowship I proposed to investigate how cells with centrosome amplification change the tumour microenvironment (TME) to promote breast cancer development.

Recent work has shown that 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 new and exciting findings showing that centrosome amplification alters secretion and could globally influence components of the tumour microenvironment (TME), such as fibroblasts and immune cells. As the TME is important for cancer cell survival and metastasis, understanding the biology behind TME changes could lead to the development of novel therapeutic strategies. Currently there is no published link between centrosome amplification and TME. Therefore, this project started an exciting and novel research avenue bridging the centrosome and the TME fields.

The objectives of this project were 1) to characterize the TME in tumours containing extra centrosomes, 2) to identify factors from the cells with extra centrosomes that induce TME changes, 3) to target cells with extra centrosomes to prevent TME changes.

I found that centrosome amplification can globally impact the TME in a murine breast cancer model. Secreted factors related to TME changes were found to be more secreted by cells with extra centrosomes. Finally, I developed a tool to assess whether ablating cells with extra centrosomes can reduce the affected TME changes.
I used 3 approaches to investigate whether centrosome abnormalities in cancer cells can affect the TME. The first approach was to characterize in vivo if centrosome amplification in cancer cells affect the TME using a mouse model for breast cancer. This showed that having centrosome amplification can indeed affect various TME components. The second objective of this project was to identify which secreted factors from cells with extra centrosomes are responsible to induce these TME changes. Using experiments were the medium from cells with extra centrosomes was analysed, I could identify factors that were more abundant in the medium of cells with extra centrosomes. For the third objective, I used a model system to ablate cells with extra centrosomes. This model was successful in vitro, but further research is needed to test its in vivo application. This is a great research tool to assess whether ablating cells with extra centrosomes within a tumour reduces the TME changes and if this will impact tumour progression.
The results from this project show that cells with extra centrosomes induce global TME changes. Thus, targeting cells with extra centrosomes means that several TME components that support tumour progression can be tackled at the same time. This could be a promising therapeutic approach in beating breast cancer. In this study I focused on breast cancer, as approximately 80% of invasive breast cancers have centrosome amplification. Since breast cancer is more prevalent in women, the results of this project will be more beneficial for women. However, centrosome amplification is a characteristic of many tumour types and our preliminary data shows that similar altered secretion is also observed in pancreatic cancer cells. Thus, our findings could also support the development of therapies for the treatment of cancer types that occur both in men and women.
centrosome amplification