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The Epithelial Polarity Program (EPP) adapts and integrates three ancient cellular machineries to construct an epithelial cell. The polarized trafficking machinery adapts the cytoskeleton and ancestral secretory and endocytic machineries to the task of sorting and delivering different plasma membrane (PM) proteins to apical and basolateral surface domains. The domain-identity machinery builds a tight junctional fence (TJ) between apical and basolateral PM domains and adapts ancient polarity proteins and polarity lipids on the cytoplasmic side of the PM, which have evolved to perform a diversity of polarity tasks across cells and species, to provide ‘identity’ to each epithelial PM domain. The 3D organization machinery utilizes adhesion molecules as positional sensors of other epithelial cells and the basement membrane and small GTPases as integrators of positional information with the activities of the domain-identity and polarized trafficking machineries. Cancer is a disease mainly of epithelial cells (90% of human cancers are carcinomas that derive from epithelial cells) that hijacks the EPP machineries, resulting in loss of epithelial polarity, which often correlates in extent with the aggressiveness of the tumor. Here, we review how the EPP integrates its three machineries and the strategies used by cancer to hijack them.

Key Points Planar cell polarity (PCP) is a polarity axis that organizes cells in the plane of the tissue. PCP is conserved in metazoans and is essential for proper development and tissue homeostasis. Asymmetric and mutually exclusive subcellular enrichment of key PCP proteins patterns cells in planar-polarized tissues. PCP proteins also coordinate planar polarity between cells and control polarized behaviours by modulating the cytoskeleton. PCP patterns develop gradually from an initially disordered state through dynamic trafficking and various feedback interactions that can influence protein localization and stability. PCP patterns seem to be globally oriented along a pre-defined axis in a given tissue. Notably, multiple mechanistic inputs may have differential influences on PCP patterning depending on developmental timing and tissue context, and may only partially overlap in different contexts. The morphogenetic events governed by PCP signalling are best understood in Drosophila melanogaster , in which the particular orientation of hairs and bristles on the fly body has served to unravel basic principles of PCP-dependent processes. Information obtained from this model has helped to better understand equivalent mechanisms in vertebrates, particularly in the context of the orientation of fluid flow mediated by multiciliated cells and cell rearrangements during convergent extension. Mutations in PCP genes have been implicated in diverse human pathologies, and the body of evidence supporting the involvement of PCP aberrations in human birth defects continues to grow rapidly. Planar cell polarity — the asymmetric distribution of proteins in the plane of a cell sheet — dictates the orientation of various subcellular structures and drives collective cell rearrangements. Better understanding of this conserved axis of polarity can shed light on the mechanisms of morphogenetic processes and explain the underlying causes of human birth defects. Planar cell polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted WNT ligands and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.

Human epithelial organoids—3D spheroids derived from adult tissue stem cells—enable investigation of epithelial physiology and disease and host interactions with microorganisms, viruses and bioactive molecules. One challenge in using organoids is the difficulty in accessing the apical, or luminal, surface of the epithelium, which is enclosed within the organoid interior. This protocol describes a method we previously developed to control human and mouse organoid polarity in suspension culture such that the apical surface faces outward to the medium (apical-out organoids). Our protocol establishes apical-out polarity rapidly (24–48 h), preserves epithelial integrity, maintains secretory and absorptive functions and allows regulation of differentiation. Here, we provide a detailed description of the organoid polarity reversal method, compatible characterization assays and an example of an application of the technology—specifically the impact of host–microbe interactions on epithelial function. Control of organoid polarity expands the possibilities of organoid use in gastrointestinal and respiratory health and disease research. The polarity of gastrointestinal organoids is reversed to study epithelial biology and host–microbe interactions. Access to the apical surface of the epithelium is increased while preserving epithelial integrity and secretory and absorptive functions.

It has long been recognized that the cell–cell adhesion receptor, E-cadherin, is an important determinant of tumor progression, serving as a suppressor of invasion and metastasis in many contexts. Yet how the loss of E-cadherin function promotes tumor progression is poorly understood. In this review, we focus on three potential underlying mechanisms: the capacity of E-cadherin to regulate β-catenin signaling in the canonical Wnt pathway; its potential to inhibit mitogenic signaling through growth factor receptors and the possible links between cadherins and the molecular determinants of epithelial polarity. Each of these potential mechanisms provides insights into the complexity that is likely responsible for the tumor-suppressive action of E-cadherin.

Malignant transformation of oral precancerous lesions is a multistep process intricately linked to the disruption of epithelial cell polarity and activation of the epithelial–mesenchymal transition (EMT) program. This study provides an integrated analysis of the polarity regulators PAR3, SCRIBBLE, and DLG7, elucidating their differential expression across normal oral mucosa (NOM), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC). By combining histopathological evaluation, immunohistochemical profiling, and whole-transcriptome sequencing, this work offers novel insights into polarity disruption as a driving mechanism in oral tumorigenesis. Formalin-fixed, paraffin-embedded (FFPE) tissue specimens were obtained from 50 habitual tobacco users from West Bengal, India. Sections were stained with hematoxylin and eosin (H&E) for histopathological assessment and classification into normal oral mucosa (NOM), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC) (well- and moderately-differentiated grades). Immunohistochemical (IHC) analysis was conducted to evaluate the expression and localization patterns of the polarity-associated proteins PAR3, SCRIBBLE, and DLG7. Complementing this, whole-transcriptome RNA sequencing was performed on biopsy specimens from an independent cohort of 25 oral cancer patients exhibiting both OED and OSCC lesions, enabling comparative gene expression profiling of the same polarity regulators. Statistical analysis using IBM SPSS (version 20.0) and Chi-square testing revealed a significant reduction or complete loss of PAR3, SCRIBBLE, and DLG7 expression in both oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), compared to their moderate to strong expression in normal oral mucosa (NOM). This study reveals a striking decline in epithelial polarity protein expression from normal oral mucosa (NOM) to oral epithelial dysplasia (OED), followed by a modest resurgence in oral squamous cell carcinoma (OSCC). The strong concordance between immunohistochemical and transcriptomic profiles—with the exception of DLG7—highlights the disruption of cell polarity as an early and central molecular event in oral carcinogenesis. Collectively, the polarity regulators PAR3, SCRIBBLE, and DLG7 emerge as promising biomarkers for early malignant transformation in oral potentially malignant disorders (OPMDs) and as potential modulators of tumor initiation, progression, and invasive behavior.

The LIN family represents a set of conserved proteins that are pivotal in the establishment of cell polarity, the development of synapses and signal transduction processes. Its members, polarity proteins LIN2, LIN7 and LIN10, interact with diverse target proteins via the PDZ domain, SH3‐GK tandem domain and PTB domain. Through these interactions, they are actively engaged in the establishment and modulation of apical‐basal polarity. Moreover, LIN2, LIN7 and LIN10, along with their associated complex LIN2/7/10, participate in the physiological phenomena of synaptic transmission and receptor localisation. In addition, from a pathological perspective, LIN2, LIN7 and LIN10 are intricately linked to the genesis and progression of type 2 diabetes, cardiovascular disorders and a wide spectrum of tumours. This review focuses on the polarity proteins LIN2, LIN7, LIN10 and their complex. It summarises the functions of these molecular domains, systematically arranges their regulatory mechanisms in both physiological and pathological contexts and summarises the current state of research on LIN2, LIN7, LIN10 and their complex. The objective is to furnish a robust theoretical foundation for the prospective utilisation of polarity proteins and their complex as cancer markers and therapeutic targets.

Epithelial cells are the most common cell type in all animals, forming the sheets and tubes that compose most organs and tissues. Apical–basal polarity is essential for epithelial cell form and function, as it determines the localization of the adhesion molecules that hold the cells together laterally and the occluding junctions that act as barriers to paracellular diffusion. Polarity must also target the secretion of specific cargoes to the apical, lateral or basal membranes and organize the cytoskeleton and internal architecture of the cell. Apical–basal polarity in many cells is established by conserved polarity factors that define the apical (Crumbs, Stardust/PALS1, aPKC, PAR-6 and CDC42), junctional (PAR-3) and lateral (Scribble, DLG, LGL, Yurt and RhoGAP19D) domains, although recent evidence indicates that not all epithelia polarize by the same mechanism. Research has begun to reveal the dynamic interactions between polarity factors and how they contribute to polarity establishment and maintenance. Elucidating these mechanisms is essential to better understand the roles of apical–basal polarity in morphogenesis and how defects in polarity contribute to diseases such as cancer.Apical–basal polarity is essential for epithelial cell form and function. Elucidating how distinct apical and basolateral compartments are established and maintained is essential to better understand the roles of apical–basal cell polarization in morphogenesis and how defects in polarity contribute to diseases such as cancer.

The microtubule-associated protein (MAP) TAU is mainly sorted into the axon of healthy brain neurons. Somatodendritic missorting of TAU is a pathological hallmark of many neurodegenerative diseases, including Alzheimer’s disease (AD). Cause, consequence and (patho)physiological mechanisms of TAU sorting and missorting are understudied, in part also because of the lack of readily available human neuronal model systems. The human neuroblastoma cell line SH-SY5Y is widely used for studying TAU physiology and TAU-related pathology in AD and related tauopathies. SH-SY5Y cells can be differentiated into neuron-like cells (SH-SY5Y-derived neurons) using various substances. This review evaluates whether SH-SY5Y-derived neurons are a suitable model for (i) investigating intracellular TAU sorting in general, and (ii) with respect to neuron subtype-specific TAU vulnerability. (I) SH-SY5Y-derived neurons show pronounced axodendritic polarity, high levels of axonally localized TAU protein, expression of all six human brain isoforms and TAU phosphorylation similar to the human brain. As SH-SY5Y cells are highly proliferative and readily accessible for genetic engineering, stable transgene integration and leading-edge genome editing are feasible. (II) SH-SY5Y-derived neurons display features of subcortical neurons early affected in many tauopathies. This allows analyzing brain region-specific differences in TAU physiology, also in the context of differential vulnerability to TAU pathology. However, several limitations should be considered when using SH-SY5Y-derived neurons, e.g., the lack of clearly defined neuronal subtypes, or the difficulty of mimicking age-related tauopathy risk factors . In brief, this review discusses the suitability of SH-SY5Y-derived neurons for investigating TAU (mis)sorting mechanisms and neuron-specific TAU vulnerability in disease paradigms.

In the twenty-first century, microglia came of age. Their remarkable ontogeny, unique functions and gene expression profile, process motility, and disease relevance have all been highlighted. Neuroscientists interested in microglia encounter an obsolete concept, M1/M2 polarization, suggesting experimental strategies that produce neither conceptual nor technical advances. Ransohoff's Perspective argues against applying this flawed paradigm. Microglial research has entered a fertile, dynamic phase characterized by novel technologies including two-photon imaging, whole-genome transcriptomic and epigenomic analysis with complementary bioinformatics, unbiased proteomics, cytometry by time of flight (CyTOF; Fluidigm) cytometry, and complex high-content experimental models including slice culture and zebrafish. Against this vivid background of newly emerging data, investigators will encounter in the microglial research literature a body of published work using the terminology of macrophage polarization, most commonly into the M1 and M2 phenotypes. It is the assertion of this opinion piece that microglial polarization has not been established by research findings. Rather, the adoption of this schema was undertaken in an attempt to simplify data interpretation at a time when the ontogeny and functional significance of microglia had not yet been characterized. Now, terminology suggesting established meaningful pathways of microglial polarization hinders rather than aids research progress and should be discarded.