The functional relationship of myoepithelial cells and macrophages in DCIS progression

Only 50% of Ductal Carcinoma in-situ (DCIS) will progress to invasive disease, but we currently cannot predict which cases will do so, leading to overdiagnosis and overtreatment. Understanding the progression of DCIS is a critical area of breast cancer research, identified as a CRUK Grand Challenge. It is well accepted that inflammation can play a critical role in changing the behaviour of breast cancer cells and tumour progression. In breast cancer, strong macrophage infiltration is commonly observed, with significant evidence to suggest correlation with poor patient outcome. Although macrophages exist within a spectrum of dynamic and evolving activation phenotypes, a subset (albeit not restricted by one set of markers) of pro-tumourigenic macrophages are known to promote angiogenesis and facilitate the metastasis of malignant cells through direct contact and cytokine mediated crosstalk. In the human breast duct myoepithelial cells fulfil a critical protective function, providing biophysical and tumour suppressive support to luminal epithelial cells that are prone to malignant transformation. Given their protective role in the healthy breast duct and progressive loss during progression to invasive ductal carcinoma, we will dissect the role of myoepithelial cells and their relationship with macrophages in the progression of DCIS. This project will use state-of-the-art 3D modelling and single-cell RNA sequencing approaches coupled with interrogation of patient samples (DCIS vs Invasive disease or DCIS with matched invasive disease), to determine the key events that mediate myoepithelial-ECM-macrophage cell cross talk in DCIS progression. We will use our genetically tractable 3D model to better understand the contribution of DCIS associated myoepithelial cells and macrophages to the microenvironment in progression. Moving away from the traditional and somewhat simplistic view of M1/M2 macrophage phenotypes, we will consider the ontogeny and contribution of tissue-resident versus monocyte derived macrophages using our single cell approach to highlight as yet unknown and rare populations. Understanding these microenvironmental features will allow us to predict progression to stratify patient management and identify microenvironmental therapeutic targets and more importantly, biomarkers of DCIS progression as a consequence of myoepithelial-macrophage interactions.