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Obesity‐Associated Adipose Stromal Cells Promote Breast Cancer Invasion through Direct Cell Contact and ECM Remodeling

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, m...

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Bibliographic Details
Published in:Advanced functional materials 2020-11, Vol.30 (48), p.n/a
Main Authors: Ling, Lu, Mulligan, Jeffrey A., Ouyang, Yunxin, Shimpi, Adrian A., Williams, Rebecca M., Beeghly, Garrett F., Hopkins, Benjamin D., Spector, Jason A., Adie, Steven G., Fischbach, Claudia
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Language:English
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Summary: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. A collagen‐embedded multicellular spheroid platform and advanced imaging approaches are used to investigate the effect of obesity‐associated adipose stromal cells (ASCs) on tumor cell migration. Direct cell–cell contact with ASCs enables collective tumor cell migration, and obese ASCs are more effective than lean ASCs. Both matrix metalloproteinase‐dependent proteolytic activity and ASC contractility are important during collective migration.
ISSN:1616-301X
1616-3028
DOI:10.1002/adfm.201910650