Resumen
The objective of this study was to investigate the role of two microenvironmental factors, namely, tumor-intrinsic hypoxia and secretome in inducing collective migration. We utilized three-dimensional (3D) discrete-sized microtumor models, which recapitulate hallmarks of transition of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Tumor-intrinsic hypoxia induced directional migration in large hypoxic microtumors while secretome from large microtumors induced radial migration in non-hypoxic microtumors. This highlights the emergence phenotypic heterogeneity and plasticity in cancer cells in response to different microenvironmental stimuli. To unravel mechanisms underlying these two distinct modes of migration, we performed differential gene expression analysis of hypoxia- and secretome-induced migratory phenotypes using non-migratory, non-hypoxic microtumors as controls. We proposed unique gene signature sets related to tumor-intrinsic hypoxia, hypoxia-induced epithelial-mesenchymal transition (EMT), as well as hypoxia-induced directional migration and secretome-induced radial migration.