Jonathan Jones

Over the last few years, many grant-awarding bodies and journals have emphasized the importance of cell line origin and validity. In this paper, the authors consider an additional issue of great importance. Are cell lines widely used as models of cancer really representative of the tumor under study? They focus on pancreatic lines as a case in point and undertake a thorough comparative analysis of the transcriptomes of commonly used lines and primary tumors. As the authors comment, their data "provide a resource for researchers to select appropriate cell lines for their tumor-specific studies".

The tissues of planarian flatworms have a remarkable ability to repair and regenerate. Cells termed neoblasts that reside in the parenchyma surrounding internal organs are the source of new cells during regeneration. However, neoblasts require positional cues in order that they are targeted to those areas where regeneration is needed. In this study, the authors identify planarian muscle as the source not only of positional information but also of extracellular matrix (ECM) production. The latter contrasts with vertebrates, where fibroblasts are the major source of ECM. The authors speculate that ECM secretion may be an "attribute" of cells exhibiting positional information and, hence, patterning of adult tissues during development and repair.

Integrins are components of cell-matrix adhesions, and function as scaffolds for various signal transduction pathways. So far no lipid ligand for integrin has been reported. Here we show that a lipid, oxysterol 25-hydroxycholesterol (25HC), directly binds to α5β1 and αvβ3 integrins to activate integrin-focal adhesion kinase (FAK) signaling. Treatment of macrophages and epithelial cells with 25HC results in an increase in activated αvβ3 integrin in podosome and focal adhesion matrix adhesion sites. Moreover, activation of pattern recognition receptor on macrophages induces secretion of 25HC, triggering integrin signaling and the production of proinflammatory cytokines such as TNF and IL-6. Thus, the lipid molecule 25HC is a physiologically relevant activator of integrins and is involved in positively regulating proinflammatory responses. Our data suggest that extracellular 25HC links innate immune inflammatory response with integrin signaling.

We all like to work out how molecular machinery is turned on but we also need to know how such machinery is switched off. This publication describes how force transmission mediated by E-cadherin is shut down. E-cadherin is important in mechanosignaling in sheets of cells, thereby playing a role in collective cell migration. Upon mechanostimulation, vinculin is recruited to sites of cell-cell interaction rich in E-cadherin. Moreover, phosphorylation of vinculin is necessary for E-cadherin to transmit forces inducing cell contractility. Here, the authors demonstrate that the protein tyrosine phosphatase SHP-2 is also activated upon E-cadherin force transmission and dephosphorylates vinculin, with a resultant reversal in cell stiffening. This allows a cycling of forces to be transmitted through a sheet of cells.

The nuclear envelope protein nesprin‐2G is a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex and is responsible for mechanical and signaling crosstalk between the nucleus and cytoskeleton. A prior study has demonstrated that nesprin‐2G knockout mice show delayed wound healing. The goal was to elucidate the mechanism underlying the delayed wound closure in this mouse model. Primary fibroblasts from wild‐type and knockout neonatal mice were isolated. Knockout cells exhibited decreased focal adhesion (FA) size, number, and intensity. Consistent with this result, FA protein expression levels were decreased in knockout cells. Additionally, knockout fibroblasts displayed an abnormal actin cytoskeleton, as evidenced by loss of TAN line formation and both cytoplasmic and peri‐nuclear actin staining. Using collective and single cell motility assays, it was found that knockout cells exhibited a reduction in both speed and directed migration. Traction force microscopy revealed that knockout fibroblasts generated fewer traction forces compared with WT fibroblasts. In summary, the data indicated that changes in actin organization and defects in FAs result in a reduced ability of knockout fibroblasts to generate traction forces needed for efficient motility.

Recent technical advances are allowing profiling of individual cells in complex tissues. Moreover, such technology is being focused on the characterization of individual cells in tumors, providing, for example, new clues to the role of stem cells in cancer survival and progression. I selected this review since it is an excellent source for those entering the cancer field and who are interested in the interrogation of single cell phenotypes in heterogeneous tumors. The authors provide a cogent description of the pluses and minuses of current technology and outline where roadblocks are arising. I particularly appreciate their comment that the field is at the point of moving past "descriptive cataloguing" as researchers generate new data regarding the functions of different cancer cell populations in tumors.

Changes in nuclear morphology contribute to regulation of complex cell properties, including differentiation and tissue elasticity. Perturbations of nuclear morphology are associated with pathologies that include, progeria, cancer, and muscular dystrophy. The mechanisms governing nuclear shape changes in healthy cells remain poorly understood, partially because there are few healthy models of nuclear shape variation. Here, we introduce nuclear branching in epidermal fin cells of Xenopus tropicalis as a model for extreme variation of nuclear morphology in a diverse population of healthy cells. We find that nuclear branching arises and elaborates during embryonic development. They contain broadly distributed marks of transcriptionally active chromatin and heterochromatin and have active cell cycles. We find that nuclear branches are disrupted by loss of filamentous actin and depend on epidermal expression of the nuclear lamina protein Lamin B1. Inhibition of nuclear branching disrupts fin morphology, suggesting that nuclear branching may be involved in fin development. This study introduces the nuclei of the fin as a powerful new model for extreme nuclear morphology in healthy cells to complement studies of nuclear shape variation in pathological contexts. © 2018. Published by The Company of Biologists Ltd.

We find that clusters of β4 integrin, organized into distinct puncta, localize along vimentin filaments within lamellipodia at the cell edge of A549 cells, as assessed by interferometric photoactivated localization microscopy. Moreover, puncta and vimentin filaments exhibit a dynamic interplay in live cells, as viewed by structured-illumination microscopy, with β4 integrin puncta that associate with vimentin persisting for longer than those that do not. Interestingly, in A549 cells β4 integrin regulates vimentin cytoskeleton organization. When β4 integrin is knocked down there is a loss of vimentin filaments from lamellipodia. However, in these conditions, vimentin filaments instead concentrate around the nucleus. Although β4 integrin organization is unaffected in vimentin-deficient A549 cells, such cells move in a less-directed fashion and exhibit reduced Rac1 activity, mimicking the phenotype of β4 integrin-deficient A549 cells. Moreover, in vimentin-deficient cells, Rac1 fails to cluster at sites enriched in α6β4 integrin heterodimers. The aberrant motility of both β4 integrin and vimentin-deficient cells is rescued by expression of active Rac1, leading us to propose that complexes of β4 integrin and vimentin act as signaling hubs, regulating cell motility behavior.