H‐Ras Transformation of Mammary Epithelial Cells Induces ERK‐Mediated Spreading on Low Stiffness Matrix
Year: 2020
Type: article
Abstract: Oncogenic transformation of mammary epithelial cells (MECs) is a critical step in epithelial-to-mesenchymal transition (EMT), but evidence also shows that MECs undergo EMT with increasing matrix stiffness; the interplay of genetic and environmental effects on EMT is not clear. To understand their combinatorial effects on EMT, premalignant MCF10A and isogenic Ras-transformed MCF10AT are cultured on polyacrylamide gels ranging from normal mammary stiffness, ≈150 Pa, to tumor stiffness, ≈5700 Pa. Though cells spread on stiff hydrogels independent of transformation, only 10AT cells exhibit heterogeneous spreading behavior on soft hydrogels. Within this mixed population, spread cells exhibit an elongated, mesenchymal-like morphology, disrupted localization of the basement membrane, and nuclear localization of the EMT transcription factor TWIST1. MCF10AT spreading is not driven by typical mechanosensitive pathways including YAP and TGF-β or by myosin contraction. Rather, ERK activation induces spreading of MCF10AT cells on soft hydrogels and requires dynamic microtubules. These findings indicate the importance of oncogenic signals, and their hierarchy with substrate mechanics, in regulating MEC EMT.
Source: Advanced Healthcare Materials
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Defense, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Division of Civil, Mechanical and Manufacturing Innovation, Congressionally Directed Medical Research Programs
Awards: G2932643688, Regulation of Breast Cancer Stem Cell by Tissue Rigidity, Biomaterial Mimicry of Dynamic Matrix Stiffening During Tumor Progression, G4119534169, Development of novel hiPSC-seeded, 3D printed vascular grafts, Predoctoral Training in Translational Musculoskeletal Research, Developing Adhesome Technology as a Physical Marker of Highly Metastatic Cells, G5850682332, Strain-Activated Signaling within Cell Adhesions Dictates Cell Fate, Collaborative Research: Heterogeneous Cancer Cell Mechanics Differentially Drives Mechanosensing and Migration, G8264406120, G8632625050
OpenAlex ID: W3000726711