Entosis is a mechanism of cell death that involves neighbor cell ingestion. This process occurs in cancers and promotes a form of cell competition, where winner cells engulf and kill losers. Entosis ...is driven by a mechanical differential that allows softer cells to eliminate stiffer cells. While this process can be induced by matrix detachment, whether other stressors can activate entosis is unknown. Here, we find that entosis is induced in adherent cells by glucose withdrawal. Glucose withdrawal leads to a bimodal distribution of cells based on their deformability, where stiffer cells appear in a manner requiring the energy-sensing AMP-activated protein kinase (AMPK). We show that loser cells with high levels of AMPK activity are eliminated by winners through entosis, which supports winner cell proliferation under nutrient-deprived conditions. Our findings demonstrate that entosis serves as a cellular response to metabolic stress that enables nutrient recovery through neighbor cell ingestion.
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•Glucose starvation induces entosis in cancer cells•AMPK regulates loser cell behavior by altering cell mechanics•Entosis supports winner cell proliferation•Long-term starvation selects for winner cells
Entosis has been shown to occur in human cancers and promotes cell competition. Hamann et al. now show that nutrient deprivation, in the form of glucose withdrawal, induces entosis to support the outgrowth of winner cells that feed off of losers.
Cellular functions, such as division and migration, require cells to undergo robust shape changes. Through their contractility machinery, cells also sense, respond, and adapt to their physical ...surroundings. In the cytoplasm, the contractility machinery organizes into higher order assemblies termed contractility kits (CKs). Using Dictyostelium discoideum, we previously identified Discoidin I (DscI), a classic secreted lectin, as a CK component through its physical interactions with the actin crosslinker Cortexillin I (CortI) and the scaffolding protein IQGAP2. Here, we find that DscI ensures robust cytokinesis through regulating intracellular components of the contractile machinery. Specifically, DscI is necessary for normal cytokinesis, cortical tension, membrane-cortex connections, and cortical distribution and mechanoresponsiveness of CortI. The dscI deletion mutants also have complex genetic epistatic relationships with CK components, acting as a genetic suppressor of cortI and iqgap1, but as an enhancer of iqgap2. This work underscores the fact that proteins like DiscI contribute in diverse ways to the activities necessary for optimal cell function.
Membrane fusion is an energy-consuming process that requires tight juxtaposition of two lipid bilayers. Little is known about how cells overcome energy barriers to bring their membranes together for ...fusion. Previously, we have shown that cell-cell fusion is an asymmetric process in which an “attacking” cell drills finger-like protrusions into the “receiving” cell to promote cell fusion. Here, we show that the receiving cell mounts a Myosin II (MyoII)-mediated mechanosensory response to its invasive fusion partner. MyoII acts as a mechanosensor, which directs its force-induced recruitment to the fusion site, and the mechanosensory response of MyoII is amplified by chemical signaling initiated by cell adhesion molecules. The accumulated MyoII, in turn, increases cortical tension and promotes fusion pore formation. We propose that the protrusive and resisting forces from fusion partners put the fusogenic synapse under high mechanical tension, which helps to overcome energy barriers for membrane apposition and drives cell membrane fusion.
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•Invasive protrusions trigger a mechanosensory response in a cell-fusion partner•Mechanosensory function of MyoII directs its accumulation at the fusogenic synapse•MyoII increases cortical tension and promotes fusion pore formation•Mechanical tension at the fusogenic synapse drives cell membrane fusion
Cell-cell fusion is induced by invasive protrusions from an “attacking” cell. Kim et al. show that the “receiving” cell mounts a mechanosensory response. The protrusive and resisting forces from two fusion partners put the fusogenic synapse under high mechanical tension, which helps to overcome energy barriers for membrane apposition and drives cell membrane fusion.
Responsible research and innovation (RRI) has come to represent a change in the relationship between science, technology and society. With origins in the democratisation of science, and the inclusion ...of ethical and societal aspects in research and development activities, RRI offers a means of integrating society and the research and innovation communities. In this article, we frame RRI activities through the lens of layers of science and technology governance as a means of characterising the context in which the RRI activity is positioned and the goal of those actors promoting the RRI activities in shaping overall governance patterns. RRI began to emerge during a time of considerable deliberation about the societal and governance challenges around nanotechnology, in which stakeholders were looking for new ways of integrating notions of responsibility in nanotechnology research and development. For this reason, this article focuses on nanotechnology as the site for exploring the evolution and growth of RRI.
Cancer progression is dependent on heightened mechanical adaptation, both for the cells' ability to change shape and to interact with varying mechanical environments. This type of adaptation is ...dependent on mechanoresponsive proteins that sense and respond to mechanical stress, as well as their regulators. Mechanoresponsive proteins are part of the mechanobiome, which is the larger network that constitutes the cell's mechanical systems that are also highly integrated with many other cellular systems, such as gene expression, metabolism, and signaling. Despite the altered expression patterns of key mechanobiome proteins across many different cancer types, pharmaceutical targeting of these proteins has been overlooked. Here, we review the biochemistry of key mechanoresponsive proteins, specifically nonmuscle myosin II, α-actinins, and filamins, as well as the partnering proteins 14-3-3 and CLP36. We also examined a wide range of data sets to assess how gene and protein expression levels of these proteins are altered across many different cancer types. Finally, we determined the potential of targeting these proteins to mitigate invasion or metastasis and suggest that the mechanobiome is a goldmine of opportunity for anticancer drug discovery and development.
Abstract
This editorial introduces the basic idea and content of the special section ‘Enemies of the future? Questioning the regimes of promising in emerging science and technology’. It sheds light ...on how visions and stories of technological futures are being produced and, in combination, have stabilized into ‘regimes of promising’ that shape emerging technoscientific domains and guide research, innovation, and governance within these domains. The special section zooms in to particular illustrative instances that reveal the dynamics of the dominant regime of promising and also reveal how they are breaking down and in some cases being replaced by alternatives. The purpose of this special section is to show the importance of regimes of promising for research and innovation policy and to stimulate further discussions on alternative regimes of promising and their ramifications.
To explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The ...BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors.
Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated.
Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues.
The data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation.
Human alteration of landscapes leads to attrition of biodiversity. Recommendations for maximizing retention of species richness typically focus on protection and preservation of large habitat ...patches. Despite a century of protection from human disturbance, 27% of the 228 bird species initially detected on Barro Colorado Island (BCI), Panama, a large hilltop forest fragment isolated by waters of Gatun Lake, are now absent. Lost species were more likely to be initially uncommon and terrestrial insectivores. Analyses of the regional avifauna, exhaustively inventoried and mapped across 24 subregions, identified strong geographical discontinuities in species distributions associated with a steep transisthmian rainfall gradient. Having lost mostly species preferring humid forests, the BCI species assemblage continues to shift from one originally typical of wetter forests toward one now resembling bird communities in drier forests. Even when habitat remnants are large and protected for 100 years, altered habitat characteristics resulting from isolation produce non-random loss of species linked with their commonness, dietary preferences and subtle climatic sensitivities.
In this book, Douglas Robinson introduces a new distinction between 'constative' and 'performative' linguistics, arguing that Austin's distinction can be used to understand linguistic methodologies. ...Constative linguistics, Robinson suggests, includes methodologies aimed at 'freezing' language as an abstract sign system, while performative linguistics explores how language is used or 'performed' in those speech situations. Robinson then tests his hypothesis on the act of translation.Drawing on a range of language scholars and theorists, Performative Linguistics consolidates the many disparate action-approaches to language into a new paradigm for the study of language.
Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific ...environments. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with α-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, α-actinin-4 exhibits a unique mechanosensory regulation that α-actinin-1 does not. This behavior is mediated, at least in part, by each protein’s actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may provide major therapeutic targeting potential for cancer metastasis.
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