Abstract
Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large‐scale coculture assay optimized to measure drug‐induced cell death, we identify tumor–stroma interactions that modulate drug sensitivity. Our data show that the chemo‐insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor–stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.
Highlights
A central challenge in medicine is selecting which drug or drug combination will be the most beneficial for a given patient
Triple-negative” breast cancers (TNBCs) can be further stratified into several definable groups which differ in chemosensitivity (Lehmann et al, 2011), it remains unclear which features are responsible for creating the variable drug sensitivity that is observed clinically
Mesenchymal-like (ML) TNBCs—which includes “mesenchymal”, “mesenchymal stemlike”, and “claudin-low” expression classes—are enriched for expression of genes related to epithelial-to-mesenchymal transition (EMT), and genes associated with stemness
Summary
A central challenge in medicine is selecting which drug or drug combination will be the most beneficial for a given patient. In cancer therapy, this decision has typically been based on the anatomical origin of the disease, in combination with drug screening to empirically identify the most efficacious compounds. Prior studies have typically highlighted the variable and unpredictable nature of tumor–stroma interactions, in which the drug sensitivity of cancer cells appears to depend on the particular combination of tumor cell, stromal cell, and drug used (Mcmillin et al, 2010). For efforts to improve precision medicine, a critical unmet need is to learn “rules” dictating how stromal cells influence the drug sensitivity of cancer cells
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