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Jones CE , Hammer AM , Cho Y , Sizemore GM , Cukierman E , Yee LD , Ghadiali SN , Ostrowski MC , Leight JL
Stromal PTEN Regulates Extracellular Matrix Organization in the Mammary Gland
Neoplasia. 2019 Jan;21(1) :132-145
PMID: 30550871    PMCID: PMC6293034    URL: https://www.ncbi.nlm.nih.gov/pubmed/30550871
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Abstract
The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression. However, it was unknown if PTEN also regulated matrix organization. To address this question, a murine model with fibroblast-specific Pten deletion was used to examine how PTEN regulates matrix remodeling. Using second harmonic generation microscopy, Pten deletion was found to promote collagen alignment parallel to the mammary duct in the normal gland and further remodeling perpendicular to the tumor edge in tumor-bearing mice. Increased alignment was observed with Pten deletion in vitro using fibroblast-derived matrices. PTEN loss was associated with fibroblast activation and increased cellular contractility, as determined by traction force microscopy. Inhibition of contractility abrogated the increased matrix alignment observed with PTEN loss. Murine mammary adenocarcinoma cells cultured on aligned matrices derived from Pten(-/-) fibroblasts migrated faster than on matrices from wild-type fibroblasts. Combined, these data demonstrate that PTEN loss in fibroblasts promotes extracellular matrix deposition and alignment independently from cancer cell presence, and this reorganization regulates cancer cell behavior. Importantly, stromal PTEN negatively correlated with collagen alignment and high mammographic density in human breast tissue, suggesting parallel function for PTEN in patients.
Notes
1476-5586 Jones, Caitlin E Hammer, Anisha M Cho, YouJin Sizemore, Gina M Cukierman, Edna Yee, Lisa D Ghadiali, Samir N Ostrowski, Michael C Leight, Jennifer L P30 CA006927/CA/NCI NIH HHS/United States P30 CA016058/CA/NCI NIH HHS/United States R01 CA113451/CA/NCI NIH HHS/United States Journal Article United States Neoplasia. 2019 Jan;21(1):132-145. doi: 10.1016/j.neo.2018.10.010. Epub 2018 Dec 12.