Title | Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Stowers RS, Shcherbina A, Israeli J, Gruber JJ, Chang J, Nam S, Rabiee A, Teruel MN, Snyder MP, Kundaje A, Chaudhuri O |
Journal | Nat Biomed Eng |
Volume | 3 |
Issue | 12 |
Pagination | 1009-1019 |
Date Published | 2019 12 |
ISSN | 2157-846X |
Keywords | Breast Neoplasms, Cell Culture Techniques, Cell Line, Tumor, Chromatin, Epithelial Cells, Epithelium, Extracellular Matrix, Female, Humans, Mechanotransduction, Cellular, Phenotype, Sp1 Transcription Factor, Transcription Factors, Tumor Microenvironment |
Abstract | In breast cancer, the increased stiffness of the extracellular matrix is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of extracellular matrix mechanics. Here, we show in a three-dimensional culture model of breast cancer that stiff extracellular matrix induces a tumorigenic phenotype through changes in chromatin state. We found that increased stiffness yielded cells with more wrinkled nuclei and with increased lamina-associated chromatin, that cells cultured in stiff matrices displayed more accessible chromatin sites, which exhibited footprints of Sp1 binding, and that this transcription factor acts along with the histone deacetylases 3 and 8 to regulate the induction of stiffness-mediated tumorigenicity. Just as cell culture on soft environments or in them rather than on tissue-culture plastic better recapitulates the acinar morphology observed in mammary epithelium in vivo, mammary epithelial cells cultured on soft microenvironments or in them also more closely replicate the in vivo chromatin state. Our results emphasize the importance of culture conditions for epigenomic studies, and reveal that chromatin state is a critical mediator of mechanotransduction. |
DOI | 10.1038/s41551-019-0420-5 |
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Alternate Journal | Nat Biomed Eng |
PubMed ID | 31285581 |
PubMed Central ID | PMC6899165 |
Grant List | R01 HL095686 / HL / NHLBI NIH HHS / United States F32 CA210431 / CA / NCI NIH HHS / United States S10 OD020141 / OD / NIH HHS / United States R01 DK101743 / DK / NIDDK NIH HHS / United States R01 DK106241 / DK / NIDDK NIH HHS / United States R37 CA214136 / CA / NCI NIH HHS / United States R01 HL122887 / HL / NHLBI NIH HHS / United States S10 RR026780 / RR / NCRR NIH HHS / United States |