Impact of early visual experience on later usage of color cues.

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.

PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers.

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.

Vulnerability of facial attractiveness perception to early and multi-year visual deprivation.

Judgments of facial attractiveness invariably accompany our perception of faces. Even neonates appear to be capable of making such judgments in a manner consistent with adults. This suggests that the processes supporting facial attractiveness require little, if any, visual experience to manifest. Here we investigate the resilience of these processes to several years of early-onset visual deprivation. Specifically, we study whether congenitally blind children treated several years after birth possess the ability to rate facial attractiveness in a manner congruent to normally sighted individuals. The data reveal significant individual variability in the way each newly sighted child perceives attractiveness. This is in marked contrast to data from normally sighted controls who exhibit strong across-subject agreement in facial attractiveness ratings. This variability may be attributable, in part, to atypical facial encoding strategies used by the newly sighted children. Overall, our results suggest that the development of facial attractiveness perception is likely to be vulnerable to early visual deprivation, pointing to the existence of a possible sensitive period early in the developmental trajectory.

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer.

Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.

ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels.

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.

Human (but not animal) motion can be recognized at first sight - After treatment for congenital blindness.

The long-standing nativist vs. empiricist debate asks a foundational question in epistemology - does our knowledge arise through experience or is it available innately? Studies that probe the sensitivity of newborns and patients recovering from congenital blindness are central in informing this dialogue. One of the most robust sensitivities our visual system possesses is to 'biological motion' - the movement patterns of humans and other vertebrates. Various biological motion perception skills (such as distinguishing between movement of human and non-human animals, or between upright and inverted human movement) become evident within the first months of life. The mechanisms of acquiring these capabilities, and specifically the contribution of visual experience to their development, are still under debate. We had the opportunity to directly examine the role of visual experience in biological motion perception, by testing what level of sensitivity is present immediately upon onset of sight following years of congenital visual deprivation. Two congenitally blind patients who underwent sight-restorative cataract-removal surgery late in life (at the ages of 7 and 20 years) were tested before and after sight restoration. The patients were shown displays of walking humans, pigeons, and cats, and asked to describe what they saw. Visual recognition of movement patterns emerged immediately upon eye-opening following surgery, when the patients spontaneously began to identify human, but not animal, biological motion. This recognition ability was evident contemporaneously for upright and inverted human displays. These findings suggest that visual recognition of human motion patterns may not critically depend on visual experience, as it was evident upon first exposure to un-obstructed sight in patients with very limited prior visual exposure, and furthermore, was not limited to the typical (upright) orientation of humans in real-life settings.

Development of Visual Memory Capacity Following Early-Onset and Extended Blindness.

It is unknown whether visual memory capacity can develop if onset of pattern vision is delayed for several years following birth. We had an opportunity to address this question through our work with an unusual population of 12 congenitally blind individuals ranging in age from 8 to 22 years. After providing them with sight surgery, we longitudinally evaluated their visual memory capacity using an image-memorization task. Our findings revealed poor visual memory capacity soon after surgery but significant improvement in subsequent months. Although there may be limits to this improvement, performance 1 year after surgery was found to be comparable with that of control participants with matched visual acuity. These findings provide evidence for plasticity of visual memory mechanisms into late childhood but do not rule out vulnerability to early deprivation. Our computational simulations suggest that a potential mechanism to account for changes in memory performance may be progressive representational elaboration in image encoding.

Resilience of temporal processing to early and extended visual deprivation.

Early visual deprivation is known to have profound consequences on the subsequent development of spatial visual processing. However, its impact on temporal processing is not well characterized. We have examined spatial and temporal contrast sensitivity functions following treatment for early and extended bilateral visual deprivation in fifteen children born with congenital cataracts in rural India. The results reveal a marked difference in post-treatment spatial and temporal sensitivities. Whereas spatial processing in newly sighted children is significantly impaired relative to age-matched controls, temporal processing exhibits remarkable resilience and is comparable to that in the control group. This difference in spatial and temporal outcomes is especially surprising given our computational analyses of video sequences which indicate a strong linkage between the spatial and temporal spectral content of natural visual inputs. We consider possible explanations for this discrepancy.

Nuclear Deformation Causes DNA Damage by Increasing Replication Stress.

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.

Hydroxyapatite mineral enhances malignant potential in a tissue-engineered model of ductal carcinoma in situ (DCIS).

While ductal carcinoma in situ (DCIS) is known as a precursor lesion to most invasive breast carcinomas, the mechanisms underlying this transition remain enigmatic. DCIS is typically diagnosed by the mammographic detection of microcalcifications (MC). MCs consisting of non-stoichiometric hydroxyapatite (HA) mineral are frequently associated with malignant disease, yet it is unclear whether HA can actively promote malignancy. To investigate this outstanding question, we compared phenotypic outcomes of breast cancer cells cultured in control or HA-containing poly(lactide-co-glycolide) (PLG) scaffolds. Exposure to HA mineral in scaffolds increased the expression of pro-tumorigenic interleukin-8 (IL-8) among transformed but not benign cells. Notably, MCF10DCIS.com cells cultured in HA scaffolds adopted morphological changes associated with increased invasiveness and exhibited increased motility that were dependent on IL-8 signaling. Moreover, MCF10DCIS.com xenografts in HA scaffolds displayed evidence of enhanced malignant progression relative to xenografts in control scaffolds. These experimental findings were supported by a pathological analysis of clinical DCIS specimens, which correlated the presence of MCs with increased IL-8 staining and ductal proliferation. Collectively, our work suggests that HA mineral may stimulate malignancy in preinvasive DCIS cells and validate PLG scaffolds as useful tools to study cell-mineral interactions.

Chromosomal instability drives metastasis through a cytosolic DNA response.

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.

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Bursting the Bubble - Nuclear Envelope Rupture as a Path to Genomic Instability?

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.