Tumour microenvironment reprogramming suppresses breast cancer

Tumours develop in complex tissue environments that consist of cancer cells, recruited host stromal and immune cells and extracellular components. The essential role of the tumour microenvironment (TME) during all stages of tumour development is now widely recognised. However, due to its dynamic and complex essence, the knowledge and implications of the cancer-stromal crosstalk remains limited. Increasing the fundamental understanding and shedding light into the different components that participate in establishing a pro-or anti-tumorigenic microenvironment is the subject of this thesis. The work presented here uses two independent approaches to modulate the early-stage formation of the TME. In chapters 3 and 4, we exploit the extrinsic abilities of contractile cancer cells to establish a better stromal crosstalk as a tool to evaluate its implications in breast cancer growth. We show that tumours initiated with lower levels of actomyosin contractility display a reduced tumorigenic potential and that this phenotype is dependent on the recruitment of a distinct TME. Flow cytometry and histology-based characterisation revealed the TME of less contractile and aggressive tumours is characterised by a differential early infiltration of cancer-associated fibroblasts and later accumulation of macrophages. Preventing macrophage recruitment during tumour development revealed the presence of functionally different macrophage subsets, which were confirmed by transcriptomics analysis. Ex-vivo functional assays showed the anti-tumorigenic abilities of macrophages relied on the interaction with CAFs. Importantly, macrophage subsets could not be characterised by canonical macrophage polarisation markers but displayed a strong prognostic value in patients. Taken together, this experimental approach revealed an anti-tumorigenic polarization phenotype of tumour-associated fibroblasts and macrophages and identified two gene signatures which have prognostic value and could be used to stratify breast cancer patients in the clinic. In chapter 5, the effects of overexpressing a microenvironmental regulator, Thrombospondin 2 (THBS2), in the growth of different subtypes of primary breast cancer was examined. The study, which combined mouse xenograft models and patient cohorts, found that THBS2 expression leads to increased tumour growth and reduced patient survival in ER-negative tumours, while not 5influencing the ER-positive subtype. Initial evidence suggests this phenotype could be due to the differential recruitment of microenvironmental components. Importantly, it reveals the breast cancer subtype-specific roles of THBS2. Overall, this PhD thesis has contributed to the understanding of how the tumour microenvironment is established and its implications for breast cancer development and progression.