Engineering Complex Breast Tumor-Stroma Models: TMPyP4-Photodynamic Therapy Is More Effective at the Metastatic Site in Breast Tumors

The breast tumor microenvironment encompasses distinct biophysical, biochemical, and cellular aspects, including a dense extracellular matrix and an array of tumor and stromal cells. The dynamics between tumor cells and their microenvironment can alter tumor behavior and impact treatment responses. Herein, tumor-stroma models (tumoroids) were engineered using dense collagen l to spatially compartmentalize a breast tumor mass in either its primary site (breast) or metastatic site (lung) to test the efficacy of photodynamic therapy (PDT) using a photosensitizer (TMPyP4) as a single treatment and in combination with doxorubicin. For tumoroids with a primary stroma, PDT efficacy was comparable for both MCF-7 and MDA-MB-231. In contrast, MCF-7 tumoroids with a metastatic stroma exhibited a greater treatment response with a 7.2-fold decrease in viability compared to the MCF-7 tumoroids with a primary stroma, whereas only a 1.1-fold decrease was seen for the MDA-MB-231 models. For MDA-MB-231 tumoroids with a primary stroma, combination treatment with PDT and doxorubicin gave the best outcomes. The viability data in the 3D models correlated with noninvasive imaging of hypoxia gradients, where hypoxia became progressively alleviated with increasing treatment efficacy. ln summary, these results highlight the necessity to model the tumor stroma as this can directly impact drug efficacy.