Fibroblast Modulation of Invasion and Chemoresistance in Triple-Negative Breast Cancer: Insights from a Two-Cell Organoid Model

Abstract

Objectives: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the absence of hormonal receptors, which limits therapeutic options. Currently, chemotherapy remains the primary treatment, although resistance often develops over time. This study aimed to develop a co-culture organoid model to investigate the role of fibroblasts in TNBC cell invasion and chemoresistance.

Methods: A two-cell organoid model using the MDA-MB-231 cell line, a model cell for TNBC, and primary human foreskin fibroblasts (HDFs) was established. Their invasion and chemotherapy response were evaluated.

Results: Our data show that the fibroblasts facilitated invasion and chemoresistance. Hence, the important role of fibroblasts in modulating TNBC cell behavior was substantiated, as the contribution of fibroblasts in the TME was shown to promote enhancement of the invasion phenotype and decrease sensitivity to chemotherapy drugs.

Conclusion: This study highlights the significance of an organoid model in reproducing the tumor microenvironment (TME); hence, it provides evidence for the involvement of fibroblasts in the formation of TNBC. Therefore, the increased drug resistance and invasion observed in organoids with fibroblasts further advocate the relevance of targeting TME components when conceiving future therapeutic strategies for TNBC