H‐Ras Transformation of Mammary Epithelial Cells Induces ERK‐Mediated Spreading on Low Stiffness Matrix
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 17, 2020
- Source ID
- 10.1002/adhm.201901366
Entities
People
- Adam J Engler
- Aditya Kumar
- Christopher Plunkett
- Gillian Grennan
- Jaime Yrastorza
- Jesse K Placone
- Yang‐hsun Hou
Organizations
- Congressionally Directed Medical Research Programs
- Division of Civil, Mechanical & Manufacturing Innovation
- National Cancer Institute
- National Heart, Lung, and Blood Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institutes of Health
- Sanford Consortium for Regenerative Medicine
- University of California, San Diego
- West Chester University of Pennsylvania