Intratumor heterogeneity in breast cancer is a significant hindrance to treatment as it promotes drug resistance and cancer progression, as well as increases the risk of disease relapse. Numerous studies have reported genetic differences during breast cancer development. However, there is a lack of understanding of the relationship between tumour composition and temporal heterogeneity in a tumour at the molecular phenotypic level. This study aims to identify how the increasing level of malignancy in breast cancer induces the epithelial-mesenchymal transition of non-tumorigenic cells. Two models were used to study indirect communications between cells by (1) extracellular vesicles (EVs) and (2) overall cellular secretions. MCF10AT, an isogenic breast epithelial cell line series, which includes four cell lines representing normal to fully malignant states (M1-M4), was used for this study. The non-tumorigenic cells (M1) were first exposed to isolated EVs from (pre-)malignant cells (M2 to M4). Then, M2 to M4 cells were seeded separately on a transwell membrane that allows secretions from the top layer to reach the bottom layer of M1 cells without physical contact between cell types. To visualize EV uptake by cells, Raman spectroscopic imaging, a label-free technique, was used. The EV and cell secretion exposed M1 cells were grown in a 3D manner to assess the malignant transition of M1 cells. Morphological and molecular changes in the M1 cells were analysed through acini development. The effect of EVs and that of the remaining secretions were probed through different degrees of exposure. This work forms a model of indirect communications between normal and cancerous cells to predict temporal heterogeneity. Establishing a clear relationship between tumour composition and temporal heterogeneity is useful for both prognosis and development of targeted and patient-specific treatments.

Distinguishing the molecular contribution from Indirect communications by 3D breast cancer models with temporal heterogeneity control

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