The nuclear envelope safeguards the genetic material inside the nucleus by separating it from the cytoplasm. Until recently, it was assumed that nuclear envelope (NE) breakdown occurs only in a ...highly controlled fashion during mitosis when the chromatin is condensed and divided between the daughter cells. However, recent studies have demonstrated that adherent and migrating cells exhibit transient NE rupture during interphase caused by compression from cytoskeletal or external forces. NE rupture results in uncontrolled exchange between the nuclear interior and cytoplasm and leads to DNA damage. In this review, we discuss the causes and consequences of NE rupture, and how NE rupture could contribute to genomic instability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of ...peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.
For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes in cell migration and cell morphology. We also used these PAD2-modulated cells to test whether PAD2 may be required for EGF-induced cell migration. To determine how PAD2 might promote tumor cell migration in vivo, we tested the effects of PAD2 inhibition on the expression of several cell migration mediators in MCF10DCIS.com xenograft tumors. In addition, we tested the effect of PAD2 inhibition on EGF-induced ductal invasion and elongation in primary mouse mammary organoids. Lastly, using a transgenic mouse model, we investigated the effects of PAD2 overexpression on mammary gland development.
Our results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells. In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin. Our mammary gland organoid study found that inhibition of PAD2 activity suppresses EGF-induced ductal invasion. In vivo, we found that PAD2 overexpression causes hyperbranching in the developing mammary gland.
Together, these results suggest that PAD2 plays a critical role in breast cancer cell migration. Our findings that EGF treatment increases protein citrullination and that PAD2 inhibition blocks EGF-induced cell migration suggest that PAD2 likely functions within the EGF signaling pathway to mediate cell migration.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
While organ‐confined prostate cancer (PCa) is mostly therapeutically manageable, metastatic progression of PCa remains an unmet clinical challenge. Resistance to anoikis, a form of cell death ...initiated by cell detachment from the surrounding extracellular matrix, is one of the cellular processes critical for PCa progression towards aggressive disease. Therefore, further understanding of anoikis regulation in PCa might provide therapeutic opportunities. Here, we discover that PCa tumours with concomitant inhibition of two tumour suppressor phosphatases, PP2A and PTEN, are particularly aggressive, having < 50% 5‐year secondary‐therapy‐free patient survival. Functionally, overexpression of PME‐1, a methylesterase for the catalytic PP2A‐C subunit, inhibits anoikis in PTEN‐deficient PCa cells. In vivo, PME‐1 inhibition increased apoptosis in in ovo PCa tumour xenografts, and attenuated PCa cell survival in zebrafish circulation. Molecularly, PME‐1‐deficient PC3 cells display increased trimethylation at lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3), a phenotype known to correlate with increased apoptosis sensitivity. In summary, our results demonstrate that PME‐1 supports anoikis resistance in PTEN‐deficient PCa cells. Clinically, these results identify PME‐1 as a candidate biomarker for a subset of particularly aggressive PTEN‐deficient PCa.
A subset of prostate cancer (PCa) tumours present simultaneous inactivation of two tumour suppressor phosphatases; phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A). PP2A is inhibited via overexpression of PME‐1. Such cancers are particularly aggressive and often relapse from standard therapy, indicating PME‐1 as a potential clinically applicable biomarker for PCa. Mechanistically, PME‐1 expression protects cancer cells from anoikis, promoting their survival outside the primary tumour.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ataxia-telangiectasia mutated (ATM) is one of the three main apical kinases at the crux of DNA damage response and repair in mammalian cells. ATM activates a cascade of downstream effector proteins ...to regulate DNA repair and cell cycle checkpoints in response to DNA double-strand breaks. While ATM is predominantly known for its role in DNA damage response and repair, new roles of ATM have recently begun to emerge, such as in regulating oxidative stress or metabolic pathways. Here, we report the surprising discovery that ATM inhibition and deletion lead to reduced expression of the nuclear envelope protein lamin A. Lamins are nuclear intermediate filaments that modulate nuclear shape, structure, and stiffness. Accordingly, inhibition or deletion of ATM resulted in increased nuclear deformability and enhanced cell migration through confined spaces, which requires substantial nuclear deformation. These findings point to a novel connection between ATM and lamin A and may have broad implications for cells with ATM mutations-as found in patients suffering from Ataxia Telangiectasia and many human cancers-which could lead to enhanced cell migration and increased metastatic potential.
Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through ...narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage. The molecular mechanisms responsible for the confined migration-induced DNA damage remain incompletely understood. Although in some cell lines, DNA damage is closely associated with nuclear envelope rupture, we show that, in others, mechanical deformation of the nucleus is sufficient to cause DNA damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA damage, unlike nuclear-envelope-rupture-induced DNA damage, occurs primarily in S/G2 phase of the cell cycle and is associated with replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication stress, possibly by increasing replication fork stalling, providing a molecular mechanism for the deformation-induced DNA damage. Thus, we have uncovered a new mechanism for mechanically induced DNA damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA damage could not only increase genomic instability in metastasizing cancer cells but could also cause DNA damage in non-migrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA damage response activation.
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•DNA damage incurred during confined migration can result from multiple mechanisms•Mechanically induced nuclear deformation is sufficient to cause DNA damage•Nuclear-deformation-associated DNA damage occurs at replication forks•Nuclear compression and deformation lead to increased replication stress
Shah et al. demonstrate a novel mechanism by which deformation of the nucleus during cell migration through tight spaces or external cell compression causes DNA damage, even in the absence of nuclear envelope rupture. The deformation-induced DNA damage primarily occurs at replication forks and is associated with increased replication stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its ...role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Impact of early visual experience on later usage of color cues Vogelsang, Marin; Vogelsang, Lukas; Gupta, Priti ...
Science (American Association for the Advancement of Science),
2024-May-24, 2024-05-24, 20240524, Volume:
384, Issue:
6698
Journal Article
Peer reviewed
Human visual recognition is remarkably robust to chromatic changes. In this work, we provide a potential account of the roots of this resilience based on observations with 10 congenitally blind ...children who gained sight late in life. Several months or years following their sight-restoring surgeries, the removal of color cues markedly reduced their recognition performance, whereas age-matched normally sighted children showed no such decrement. This finding may be explained by the greater-than-neonatal maturity of the late-sighted children's color system at sight onset, inducing overly strong reliance on chromatic cues. Simulations with deep neural networks corroborate this hypothesis. These findings highlight the adaptive significance of typical developmental trajectories and provide guidelines for enhancing machine vision systems.
In his 1872 monograph, Charles Darwin posited that "… the habit of expressing our feelings by certain movements, though now rendered innate, had been in some manner gradually acquired."1 Nearly 150 ...years later, researchers are still teasing apart innate versus experience-dependent contributions to expression recognition. Indeed, studies have shown that face detection is surprisingly resilient to early visual deprivation,2,3,4,5 pointing to plasticity that extends beyond dogmatic critical periods.6,7,8 However, it remains unclear whether such resilience extends to downstream processing, such as the ability to recognize facial expressions. The extent to which innate versus experience-dependent mechanisms contribute to this ability has yet to be fully explored.9,10,11,12,13 To investigate the impact of early visual experience on facial-expression recognition, we studied children with congenital cataracts who have undergone sight-correcting treatment14,15 and tracked their longitudinal skill acquisition as they gain sight late in life. We introduce and explore two potential facilitators of late-life plasticity: the availability of newborn-like coarse visual acuity prior to treatment16 and the privileged role of motion following treatment.4,17,18 We find that early visual deprivation does not preclude partial acquisition of facial-expression recognition. While rudimentary pretreatment vision is sufficient to allow a low level of expression recognition, it does not facilitate post-treatment improvements. Additionally, only children commencing vision with high visual acuity privilege the use of dynamic cues. We conclude that skipping typical visual experience early in development and introducing high-resolution imagery late in development restricts, but does not preclude, facial-expression skill acquisition and that the representational mechanisms driving this learning differ from those that emerge during typical visual development.In his 1872 monograph, Charles Darwin posited that "… the habit of expressing our feelings by certain movements, though now rendered innate, had been in some manner gradually acquired."1 Nearly 150 years later, researchers are still teasing apart innate versus experience-dependent contributions to expression recognition. Indeed, studies have shown that face detection is surprisingly resilient to early visual deprivation,2,3,4,5 pointing to plasticity that extends beyond dogmatic critical periods.6,7,8 However, it remains unclear whether such resilience extends to downstream processing, such as the ability to recognize facial expressions. The extent to which innate versus experience-dependent mechanisms contribute to this ability has yet to be fully explored.9,10,11,12,13 To investigate the impact of early visual experience on facial-expression recognition, we studied children with congenital cataracts who have undergone sight-correcting treatment14,15 and tracked their longitudinal skill acquisition as they gain sight late in life. We introduce and explore two potential facilitators of late-life plasticity: the availability of newborn-like coarse visual acuity prior to treatment16 and the privileged role of motion following treatment.4,17,18 We find that early visual deprivation does not preclude partial acquisition of facial-expression recognition. While rudimentary pretreatment vision is sufficient to allow a low level of expression recognition, it does not facilitate post-treatment improvements. Additionally, only children commencing vision with high visual acuity privilege the use of dynamic cues. We conclude that skipping typical visual experience early in development and introducing high-resolution imagery late in development restricts, but does not preclude, facial-expression skill acquisition and that the representational mechanisms driving this learning differ from those that emerge during typical visual development.
Human visual memory capacity has a rapid developmental progression. Here we examine whether image semantics modulate this progression. We assessed the performance of children (6–14 years) and young ...adults (19–36 years) on a visual memory task using real‐world (or meaningful) as well as image sets, which were matched in low‐level image attributes. For real images, we find comparable performance across the two age groups, consistent with previously reported results. However, for images, we find a clear age‐related difference indicating greater reliance of children's memory processes on semantics, suggesting that strategies for encoding patterns keep improving even into late childhood. We complemented these studies with computational experiments designed to examine the role of increasing experience with real‐world images on real and image encoding, to examine whether the observed age‐related differences, as well as the general privilege of real over images, can emerge directly through experience with meaningful images. Our results provide support for this possibility and set the stage for a finer‐grained investigation of the timeline along which children's memory capacity for images reaches adult levels.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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