Modelling breast cancer heterogeneity: Effects of stromal compartments on sub-clonal decision-making

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Significant progress has been made in the diagnosis and treatment of breast cancer (BC); however, tumour heterogeneity remains a considerable challenge in the design of effective therapies. The coexistence of subpopulations of cancer cells within one tumour with different genetic and phenotypic characteristic leads to negative treatment impact, ultimate recurrence risk and poor patient survival. Despite this identified impact on treatment efficacy the subject of cancer heterogeneity is often neglected. To this date, the implementation of the heterogeneity aspect into cancer studies is very limited due to the lack of adequate models or longitudinal data. So far, this issue is either tackled by analysing Patient-Derived Xenografts (PDXs) in mouse models or through application of computational biology for the reconstruction of cancer evolution and its heterogeneity from multiregional biopsies. BC mortality essentially results from metastases to distant sites and secondary tumours, which cellular and genetic profiles differ from the original tumour bulk data. Unfortunately, detailed longitudinal assessments of metastases composition are currently not available. Nevertheless, lately, the understanding of the importance of heterogeneity within the same tumour or between patients is steadily growing and is recognised to be a major factor in future diagnosis and treatment. In our laboratory, we currently are developing a spatio-temporal resolving in vitro 3D model for heterogeneity that we apply to understand the onset and progression of BC better. We are specifically interested in understanding the hierarchy of known and putative BC drivers in a multiclonal competing environment. Therefore, we develop a multigene-multifluorophore construct that allows us to induce specific cancer signatures and to trace different lineages in real-time. Our current model investigates a panel of 25 genes in different multigene-combinations which can be found in most BC cases independent of their molecular subtype. This panel covers genetic signatures of about 86% of all BC cases according to the cBioPortal data bank. Nevertheless, due to the constructs unique bio brick building system, the panel can easily be extended or exchanged. Having developed a model for BC heterogeneity and tumour evolution this study focuses on the interaction of the heterogeneous tumour mass with the microenvironment and the contribution of stromal cells, specifically endothelial cells, fibroblasts and resident or requited macrophages on tumour development and progression.We hypothesis that different sub-clonal populations will have specific and distinct interactions with each other and with the microenvironment itself depending on its composition. Relating to heterogeneity in BC the aim is to study the interaction of a multiclonal tumour in absence and presence of tumour microenvironment in vitro combining the RAFT system with a multiscale 3D model or in vivo using intravital imaging in mice. Ultimately, the study will 1) reveal the hierarchy of BC drivers and its possible variation depending on microenvironmental components; 2) consult existing computational heterogeneity and tumour progression models and develop one that captures this complex crosstalk; 3) analyse in vivo sub-clonal interactions with each other and with the microenvironment and later on sub-clonal preference for a secondary niche. Taking together, the study will test the hypothesis that sub-clonal variation in cellular profiles and behaviour in a heterogeneous tumour will lead to different survival and progression programmes and that these advantages in tumour development will change with the composition of the surrounding microenvironment.