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

## TL;DR

This study shows that photodynamic therapy using TMPyP4 is more effective against breast tumors in the lung compared to the breast, highlighting the importance of modeling the tumor microenvironment.

## Contribution

The study introduces engineered 3D tumor-stroma models to evaluate photodynamic therapy efficacy in different tumor sites.

## Key findings

- TMPyP4-based photodynamic therapy was more effective in metastatic lung tumoroids than in primary breast tumoroids.
- Combination therapy with photodynamic treatment and doxorubicin showed best outcomes for MDA-MB-231 tumoroids with a primary stroma.
- Hypoxia imaging correlated with treatment efficacy in 3D tumor models.

## Abstract

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.