NOVEL ROLES OF EXTRACELLULAR MATRIX AND NONMUSCLE MYOSIN II IN REGULATING EPITHELIAL MIGRATION AND PROLIFERATION

Extracellular matrix (ECM);Myosin II;Proliferation;Migration;Mammary epithelium;Cell Biology

Nguyen-Ngoc, Kim-VyCoulombe, Pierre A. ;

Johns Hopkins University

关键词: Extracellular matrix (ECM);    Myosin II;    Proliferation;    Migration;    Mammary epithelium;    Cell Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39506/NGUYEN-NGOC-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

The extracellular matrix (ECM) provides physical support for tissue development and is co-opted in cancer. The mammary gland includes two distinct types of ECMs: a collagen I-rich stroma, and basement membrane (BM) that separates epithelial tissue from the stroma. The ECM is continuously remodeled to control tissue integrity while its abnormal remodeling correlates with breast cancer metastasis. However, how ECM microenvironments differentially regulate epithelial cell behavior of normal and tumor tissues remains elusive. We explanted ductal groups, called organoids, from normal and tumor mammary epithelium into 3D gels of BM (Matrigel) and collagen I. We found that the local ECM primarily determined cell migratory behavior. While collagen I induced protrusive invasion in normal and tumor organoids while they grew indolently in Matrigel. However, different from tumor cells that persistently invaded, normal cells ceased to protrude, and restored epithelial structure. Inhibition of actomyosin contractility abolished the epithelial reorganization. Moreover, the addition of Matrigel suppressed collagen I-triggered invasion. Interestingly, we identified a mix of Matrigel and collagen I as a better ECM microenvironment to recapitulate branching morphogenesis.We next aimed to uncover how myosin II-mediated contractility regulates epithelial reorganization. We used Cre-lox-based gene deletion to induce the deletion of non-muscle myosin II (NMII) isoforms. Surprisingly, concurrent deletion of NMIIA and NMIIB (NMIIA,B) stimulated excessive proliferation in quiescent and actively growing epithelial tissues. The genetic mosaic analysis revealed that the hyper-proliferation was a non-cell autonomous effect. Our data unravel a novel cooperative role of NMIIA,B as negative regulators for cell proliferation and tissue growth.