Cells Forming Acini
Berkeley Lab researchers have discovered a rotational motion in human breast cells that continues through mitosis and enables the cells and their progeny to form sphere-shaped acini.
59 BASIC BIOLOGICAL SCIENCES↗
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Δ133p53 coordinates ECM-driven morphogenesis and gene expression in 3-dimensional mammary epithelial acini
Growing evidence indicates that p53 has a crucial role in normal tissue development. The role of the canonical p53 (p53α) and its 12± isoforms in development and homeostasis of healthy tissue remains poorly understood. Here we demonstrate that Δ133p53, three short isoforms of p53 isoform, responds specifically to laminin-111 and plays an important regulatory role in formation of mammary organoids in concert with p53α. We demonstrate that down-modulation of Δ133p53 isoforms leads to changes in gene expression of extracellular matrix molecules: fibronectin (FN), EDA+-FN, laminin α5, and laminin α3 in human breast epithelial cells. These changes resulted in increased actin stress fibers and enhanced migratory behavior of cells in 2-dimensional culture. We found that α5β1-integrin coupled with the extracellularly deposited EDA+-FN activates Akt signaling pathway in 3-dimensional (3D) culture when Δ133p53 is dysregulated. Cells that do not express detectable Δ133p53 isoforms or express low levels of these isoforms failed to form polarized structures in 3D. These results uncover that Δ133p53 isoforms coordinate expression and deposition of organ-specific ECM molecules that are critical for maintenance of tissue architecture and function.
Lee, Sun-Young (ORCID:000000034970241X)↗
Multicellular Architecture of Malignant Breast Epithelia Influences Mechanics
Cell-matrix and cell-cell mechanosensing are important in many cellular processes, particularly for epithelial cells. A crucial question, which remains unexplored, is how the mechanical microenvironment is altered as a result of changes to multicellular tissue structure during cancer progression. In this study, we investigated the influence of the multicellular tissue architecture on mechanical properties of the epithelial component of the mammary acinus. Using creep compression tests on multicellular breast epithelial structures, we found that pre-malignant acini with no lumen (MCF10AT) were significantly stiffer than normal hollow acini (MCF10A) by 60%. This difference depended on structural changes in the premalignant acini, as neither single cells nor normal multicellular acini tested before lumen formation exhibited these differences. To understand these differences, we simulated the deformation of the acini with different multicellular architectures and calculated their mechanical properties; our results suggest that lumen filling alone can explain the experimentally observed stiffness increase. We also simulated a single contracting cell in different multicellular architectures and found that lumen filling led to a 20% increase in the "perceived stiffness" of a single contracting cell independent of any changes to matrix mechanics. Our results suggest that lumen filling in carcinogenesis alters the mechanical microenvironment in multicellular epithelial structures, a phenotype that may cause downstream disruptions to mechanosensing.
59 BASIC BIOLOGICAL SCIENCES↗
β1 and β4 integrins: from breast development to clinical practice
Following a highly dynamic and complex dialogue between the epithelium and the surrounding microenvironment, the mammary gland develops into a branching structure during puberty, buds during pregnancy, forms intricate polar acini during lactation and, once the babies are weaned, remodels and involutes. At every stage of menstrual and pregnancy cycles, interactions between the cells and the extracellular matrix (ECM) and homotypic and heterotypic cell–cell interactions give rise to the architecture and function of the gland at that junction. These orchestrated programs would not be possible without the important role of the ECM receptors, integrins being the prime examples. The ECM–integrin axis regulates many crucial cellular functions including survival, migration and quiescence; the imbalance in any of these processes could contribute to oncogenesis. In this review we spotlight the involvement of two prominent integrin subunits, β1 and β4 integrins, in cross-talk with tyrosine kinase receptors, and we discuss the roles of these integrin subunits in the biology of normal breast differentiation and as potential prognostic and therapeutic targets in breast cancer.
60 APPLIED LIFE SCIENCES↗
Deep nuclear invaginations linked to cytoskeletal filaments: Integrated bioimaging of epithelial cells in 3D culture
The importance of context in regulation of gene expression is now an accepted principle; yet the mechanism by which the microenvironment communicates with the nucleus and chromatin in healthy tissues is poorly understood. A functional role for nuclear and cytoskeletal architecture is suggested by the phenotypic differences observed between epithelial and mesenchymal cells. Capitalizing on recent advances in cryogenic techniques, volume electron microscopy, and super-resolution light microscopy, we studied human mammary epithelial cells in 3D cultures forming growth-arrested acini. Intriguingly, we found deep nuclear invaginations and tunnels traversing the nucleus, encasing cytoskeletal actin and/or intermediate filaments, which connect to the outer nuclear envelope. The cytoskeleton is connected also to both other cells via desmosome adhesion complexes and to the cell's ECM via hemidesmosomes. This finding supports a physical/mechanical link from the desmosomes and hemidesmosomes to the nucleus, which previously was hypothesized but now is visualized for the first time. These unique structures including the nuclear invaginations and the cytoskeletal connectivity to the cell nucleus is consistent with a dynamic reciprocity between the nucleus and the outside of epithelial cells and tissues.
59 BASIC BIOLOGICAL SCIENCES↗
NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres (‘acini’), the malignant T4-2 cells that form large tumor-like clusters, and the ‘phenotypically reverted’ T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture.
59 BASIC BIOLOGICAL SCIENCES↗