Celeste M. Nelson

Bio: Celeste M. Nelson is an academic researcher from Princeton University. The author has contributed to research in topics: Morphogenesis & Extracellular matrix. The author has an hindex of 57, co-authored 158 publications receiving 15507 citations. Previous affiliations of Celeste M. Nelson include Johns Hopkins University & Massachusetts Institute of Technology.

Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability

Abstract: The tumour microenvironment can be a potent carcinogen, not only by facilitating cancer progression and activating dormant cancer cells, but also by stimulating tumour formation 1 . We have previously investigated stromelysin-1/matrix metalloproteinase-3 (MMP-3), a stromal enzyme upregulated in many breast tumours 2 , and found that MMP-3 can cause epithelial–mesenchymal transition (EMT) and malignant transformation in cultured cells 3–5 , and genomically unstable mammary carcinomas in transgenic mice 3 . Here we explain the molecular pathways by which MMP-3 exerts these effects: exposure of mouse mammary epithelial cells to MMP-3 induces the expression of an alternatively spliced form of Rac1, which causes an increase in cellular reactive oxygen species (ROS). The ROS stimulate the expression of the transcription factor Snail and EMT, and cause oxidative damage to DNA and genomic instability. These findings identify a previously undescribed pathway in which a component of the breast tumour microenvironment alters cellular structure in culture and tissue structure in vivo, leading to malignant transformation. Cancer is characterized by a progressive series of alterations that disrupt cell and tissue homeostasis. Whereas many of these alterations can be induced by specific mutations, faulty signals from the microenvironment also can act as inducers of tumour development

Of Extracellular Matrix, Scaffolds, and Signaling: Tissue Architecture Regulates Development, Homeostasis, and Cancer

Abstract: The microenvironment influences gene expression so that the behavior of a cell is largely determined by its interactions with the extracellular matrix, neighboring cells, and soluble local and systemic cues. We describe the essential roles of context and organ structure in directing mammary gland development and differentiated function and in determining the response to oncogenic insults, including mutations. We expand on the concept of “dynamic reciprocity” to present an integrated view of development, cancer, and aging and posit that genes are like the keys on a piano: Although they are essential, it is the context that makes the music.

Emergent patterns of growth controlled by multicellular form and mechanics.

Abstract: Spatial patterns of cellular growth generate mechanical stresses that help to push, fold, expand, and deform tissues into their specific forms. Genetic factors are thought to specify patterns of growth and other behaviors to drive morphogenesis. Here, we show that tissue form itself can feed back to regulate patterns of proliferation. Using microfabrication to control the organization of sheets of cells, we demonstrated the emergence of stable patterns of proliferative foci. Regions of concentrated growth corresponded to regions of high tractional stress generated within the sheet, as predicted by a finite-element model of multicellular mechanics and measured directly by using a micromechanical force sensor array. Inhibiting actomyosin-based tension or cadherin-mediated connections between cells disrupted the spatial pattern of proliferation. These findings demonstrate the existence of patterns of mechanical forces that originate from the contraction of cells, emerge from their multicellular organization, and result in patterns of growth. Thus, tissue form is not only a consequence but also an active regulator of tissue growth.

Mechanical tugging force regulates the size of cell–cell junctions

Abstract: Actomyosin contractility affects cellular organization within tissues in part through the generation of mechanical forces at sites of cell–matrix and cell–cell contact While increased mechanical loading at cell–matrix adhesions results in focal adhesion growth, whether forces drive changes in the size of cell–cell adhesions remains an open question To investigate the responsiveness of adherens junctions (AJ) to force, we adapted a system of microfabricated force sensors to quantitatively report cell–cell tugging force and AJ size We observed that AJ size was modulated by endothelial cell–cell tugging forces: AJs and tugging force grew or decayed with myosin activation or inhibition, respectively Myosin-dependent regulation of AJs operated in concert with a Rac1, and this coordinated regulation was illustrated by showing that the effects of vascular permeability agents (S1P, thrombin) on junctional stability were reversed by changing the extent to which these agents coupled to the Rac and myosin-dependent pathways Furthermore, direct application of mechanical tugging force, rather than myosin activity per se, was sufficient to trigger AJ growth These findings demonstrate that the dynamic coordination of mechanical forces and cell–cell adhesive interactions likely is critical to the maintenance of multicellular integrity and highlight the need for new approaches to study tugging forces

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。