RT Journal Article
SR Electronic
T1 Fibroblasts from metastatic sites induce broad-spectrum drug desensitization via modulation of mitochondrial priming
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 197376
DO 10.1101/197376
A1 Benjamin D. Landry
A1 Thomas Leete
A1 Ryan Richards
A1 Peter Cruz-Gordillo
A1 Gary Ren
A1 Alyssa D. Schwartz
A1 Shelly R. Peyton
A1 Michael J. Lee
YR 2017
UL http://biorxiv.org/content/early/2017/10/02/197376.abstract
AB 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 what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor micro-environment. Using a large-scale co-culture 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 cell intrinsic, but rather a product of tumor-fibroblast interactions. Additionally, we find that fibroblast cells influence tumor drug response in two distinct and divergent manners, which were predicable based on the anatomical origin from which the fibroblasts were harvested. These divergent phenotypes result from modulation of “mitochondrial priming” of tumor cells, caused by secretion of inflammatory cytokines, such as IL6 and IL8, from stromal cells.