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Obesity increases the risk and worsens the prognosis for breast cancer due, in part, to altered adipose stromal cell (ASC) behavior. Whether ASCs from obese individuals increase migration of breast cancer cells relative to their lean counterparts, however, remains unclear. To test this connection, multicellular spheroids composed of MCF10A‐derived tumor cell lines of varying malignant potential and lean or obese ASCs are embedded into collagen scaffolds mimicking the elastic moduli of interstitial breast adipose tissue. Confocal image analysis suggests that tumor cells alone migrate insignificantly under these conditions. However, direct cell‐cell contact with either lean or obese ASCs enables them to migrate collectively, whereby obese ASCs activate tumor cell migration more effectively than their lean counterparts. Time‐resolved optical coherence tomography imaging suggests that obese ASCs facilitate tumor cell migration by mediating contraction of local collagen fibers. Matrix metalloproteinase (MMP)‐dependent proteolytic activity significantly contributes to ASC‐mediated tumor cell invasion and collagen deformation. However, ASC contractility is also important, as co‐inhibition of both MMPs and contractility is necessary to completely abrogate ASC‐mediated tumor cell migration. These findings imply that obesity‐mediated changes of ASC phenotype may impact tumor cell migration and invasion with potential implications for breast cancer malignancy in obese patients. [ABSTRACT FROM AUTHOR]

Altered microarchitecture of collagen type I is a hallmark of wound healing and cancer that is commonly attributed to myofibroblasts. However, it remains unknown which effect collagen microarchitecture has on myofibroblast differentiation. Here, we combined experimental and computational approaches to investigate the hypothesis that the microarchitecture of fibrillar collagen networks mechanically regulates myofibroblast differentiation of adipose stromal cells (ASCs) independent of bulk stiffness. Collagen gels with controlled fiber thickness and pore size were microfabricated by adjusting the gelation temperature while keeping their concentration constant. Rheological characterization and simulation data indicated that networks with thicker fibers and larger pores exhibited increased strain-stiffening relative to networks with thinner fibers and smaller pores. Accordingly, ASCs cultured in scaffolds with thicker fibers were more contractile, expressed myofibroblast markers, and deposited more extended fibronectin fibers. Consistent with elevated myofibroblast differentiation, ASCs in scaffolds with thicker fibers exhibited a more proangiogenic phenotype that promoted endothelial sprouting in a contractility-dependent manner. Our findings suggest that changes of collagen microarchitecture regulate myofibroblast differentiation and fibrosis independent of collagen quantity and bulk stiffness by locally modulating cellular mechanosignaling. These findings have implications for regenerative medicine and anticancer treatments. [ABSTRACT FROM AUTHOR]

Extracellular Matrix Remodelling: Obesity-Associated Adipose Stromal Cells Promote Breast Cancer Invasion through Direct Cell Contact and ECM Remodeling (Adv. Funct. Keywords: collagen; extracellular matrix remodeling; obesity; optical coherence tomography; tumor invasion EN collagen extracellular matrix remodeling obesity optical coherence tomography tumor invasion 1 1 1 11/27/20 20201125 NES 201125 In article number 1910650, Claudia Fischbach and co-workers combine collagen-embedded multicellular spheroids and advanced imaging to investigate the effect of adipose stromal cells (ASCs) on tumor cell invasion as a function of obesity. Obese ASCs increase collective tumor cell migration relative to lean ASCs by stimulating proteolytic and contractility-dependent collagen remode ling, providing insights into how obesity promotes breast cancer malignancy. [Extracted from the article]