Changes in tumor tissue organization in collagen-I sensitize cells to ionizing radiation in an ex vivo model of solid mammary tumor growth and local invasion.

摘要

Breast cancer is a disease involving changes in epithelial cell polarity and tissue organization. We are interested in how changes in tumor tissue architecture within a dynamic microenviron-ment may impact the response to targeted therapy. Previously, we showed that the three-dimensional (3D) organization of reconstituted Her2eu-driven mouse mammary tumors was disrupted following the addition of collagen-l ex vivo. Tumor cells from MMTV-Her2eu mice normally form highly proliferative, non-invasive tumor-like spheres when cultured on a thick bed of Matrigel reconstituted basement membrane (Fig. 1A and B). Histologically, these multicel-lular structures resemble non-invasive tumors which form during early stages of transformation in the MMTV-Her2/ neu mouse mammary gland (Fig. 1C). When presented with an overlay of col-lagen-I, however, cells at the margins of the reconstituted tumors undergo rapid changes in cell shape and behavior which are hallmarks of an epithelial-to-mesen-chymal-like transition, including loss of E-cadherin from the cell-cell membrane junctions, the transition to an elongated, highly invasive single-cell morphology, and the dissemination or "scattering" of the cells away from their compact 3D arrangement (Fig. ID-K).