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Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.

Plasticity among cell lineages is a fundamental, but poorly understood, property of regenerative tissues. In the gut tube, the small intestine absorbs nutrients, whereas the colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screening, we identify MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrains colonic plasticity. MTA2 loss in the adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-occupies DNA with HNF4A, an activating pan-intestinal transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic chromatin, and accumulation on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through an HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages, and their release unleashes plasticity.

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC. [ABSTRACT FROM AUTHOR]

Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial–mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial–mesenchymal transition (EMT), partial EMT, and mesenchymal–epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor‐β, Wnt/β‐catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune‐related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP‐driven tumor deterioration. Additionally, we explore the potential technique for EMP‐based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP. [ABSTRACT FROM AUTHOR]

Since its identification as a marker for advanced melanoma in the 1980s, CD146 has been found to have multiple functions in both physiological and pathological processes, including embryonic development, tissue repair and regeneration, tumor progression, fibrosis disease, and inflammations. Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or co-receptor in these processes. This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis, prognosis, and targeted therapy. To better comprehend the versatile roles of CD146, we have summarized its research history and synthesized findings from numerous reports, proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development, regeneration, and various diseases. Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases. Therefore, the development of therapy targeting CD146 holds significant practical value. [ABSTRACT FROM AUTHOR]

Acute-on-chronic liver failure (ACLF) is a group of clinical syndromes related to severe acute liver function damage and multiple organ failure caused by various acute inducing factors on the basis of chronic liver disease. Due to its serious condition, rapid progression and high mortality, it has attracted more and more attention. Recent studies have shown that the pathogenesis of ACLF mainly includes direct injury and immune injury. As the main immune cells in the liver, the immunoregulatory role of liver macrophages in ACLF has been increasingly recognized. Liver macrophages have excellent phenotype conversion function and plasticity characteristics under the influence of epigenetic reprogramming or local microenvironment. This adaptive expression ability can use key mediators to promote the early conversion of anti-inflammatory phenotype to alleviate liver injury. A large number of studies have shown that liver macrophages have a certain potential in reversing the process of ACLF. Therefore, from the perspective of the plasticity characteristics of liver macrophages, this paper expounds the role of liver macrophages in ACLF and the research on the intervention of ACLF disease process, and summarizes its potential significance in the treatment of ACLF. [ABSTRACT FROM AUTHOR]

Objective To investigate the regulatory effect of extracellular matrix (ECM) stiffness on the plasticity of human prostate cancer cells (LNCaP). Methods Human LNCaP cells were cultured in ECM culture dishes with four types of stiffness (i.e., Young’s modulus of 3 GPa [group A], 20 kPa [group B], 6 kPa [group C], and 1 kPa [group D]) for one week. The morphology of cells on substrates of different stiffness values was observed for each group using bright-field microscopy and fluorescence microscopy. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression levels of luminal cell marker genes (AR, CK8, CK18, and PSA), basal cell marker genes (CK5 and P63), and proliferative genes (KI67 and PCNA) in each group. Results Bright-field microscopy and fluorescence microscopy showed that human LNCaP cells in group A exhibited typically spread epithelial cell morphology, whereas the cells in groups B to D showed the state of agglomerated small cell sheets, and the cells in group D formed a three-dimensional organ-like structure. RT-qPCR results showed that there were no significant differences between the four groups in the expression levels of KI67 and P63 genes in human LNCaP cells (P>0.05). The expression level of PCNA gene in group B was significantly higher than that in groups A and C (F=34.96,t=8.39,6.37,P

Abstract DNA topoisomerase II alpha (TOP2A) expression, gene alterations, and enzyme activity have been studied in various malignant tumors. Abnormal elevation of TOP2A expression is considered to be related to the development of non-small cell lung cancer (NSCLC). However, its association with tumor metastasis and its mode of action remains unclear. Bioinformatics, real-time quantitative PCR, immunohistochemistry and immunoblotting were used to detect TOP2A expression in NSCLC tissues and cells. Cell migration and invasion assays as well as cytoskeletal staining were performed to analyze the effects of TOP2A on the motility, migration and invasion ability of NSCLC cells. Cell cycle and apoptosis assays were used to verify the effects of TOP2A on apoptosis as well as cycle distribution in NSCLC. TOP2A expression was considerably upregulated in NSCLC and significantly correlated with tumor metastasis and the occurrence of epithelial–mesenchymal transition (EMT) in NSCLC. Additionally, by interacting with the classical ligand Wnt3a, TOP2A may trigger the canonical Wnt signaling pathway in NSCLC. These observations suggest that TOP2A promotes EMT in NSCLC by activating the Wnt/β-catenin signaling pathway and positively regulates malignant events in NSCLC, in addition to its significant association with tumor metastasis. TOP2A promotes the metastasis of NSCLC by stimulating the canonical Wnt signaling pathway and inducing EMT. This study further elucidates the mechanism of action of TOP2A, suggesting that it might be a potential therapeutic target for anti-metastatic therapy.

DNA topoisomerase II alpha (TOP2A) expression, gene alterations, and enzyme activity have been studied in various malignant tumors. Abnormal elevation of TOP2A expression is considered to be related to the development of non-small cell lung cancer (NSCLC). However, its association with tumor metastasis and its mode of action remains unclear. Bioinformatics, real-time quantitative PCR, immunohistochemistry and immunoblotting were used to detect TOP2A expression in NSCLC tissues and cells. Cell migration and invasion assays as well as cytoskeletal staining were performed to analyze the effects of TOP2A on the motility, migration and invasion ability of NSCLC cells. Cell cycle and apoptosis assays were used to verify the effects of TOP2A on apoptosis as well as cycle distribution in NSCLC. TOP2A expression was considerably upregulated in NSCLC and significantly correlated with tumor metastasis and the occurrence of epithelial–mesenchymal transition (EMT) in NSCLC. Additionally, by interacting with the classical ligand Wnt3a, TOP2A may trigger the canonical Wnt signaling pathway in NSCLC. These observations suggest that TOP2A promotes EMT in NSCLC by activating the Wnt/β-catenin signaling pathway and positively regulates malignant events in NSCLC, in addition to its significant association with tumor metastasis. TOP2A promotes the metastasis of NSCLC by stimulating the canonical Wnt signaling pathway and inducing EMT. This study further elucidates the mechanism of action of TOP2A, suggesting that it might be a potential therapeutic target for anti-metastatic therapy. [ABSTRACT FROM AUTHOR]

In the last decade tight junction proteins exposed at the surface of liver or cancer cells have been uncovered as mediators of liver disease biology: Claudin-1 and Occludin are host factors for hepatitis C virus entry and Claudin-1 has been identified as a driver for liver fibrosis and hepatocellular carcinoma (HCC). Moreover, Claudins have emerged as therapeutic targets for liver disease and HCC. CLDN1 expression is upregulated in liver fibrosis and HCC. Monoclonal antibodies (mAbs) targeting Claudin-1 have completed preclinical proof-of-concept studies for treatment of liver fibrosis and HCC and are currently in clinical development for advanced liver fibrosis. Claudin-6 overexpression is associated with an HCC aggressive phenotype and treatment resistance. Claudin-6 mAbs or chimeric antigen receptor-T cells therapies are currently being clinically investigated for Claudin-6 overexpressing tumors. In conclusion, targeting Claudin proteins offers a novel clinical opportunity for the treatment of patients with advanced liver fibrosis and HCC. [ABSTRACT FROM AUTHOR]

9p21.3 locus polymorphisms have the strongest correlation with coronary artery disease, but as a noncoding locus, disease connection is enigmatic. The lncRNA ANRIL found in 9p21.3 may regulate vascular smooth muscle cell (VSMC) phenotype to contribute to disease risk. We observed significant heterogeneity in induced pluripotent stem cell-derived VSMCs from patients homozygous for risk versus isogenic knockout or nonrisk haplotypes. Subpopulations of risk haplotype cells exhibited variable morphology, proliferation, contraction, and adhesion. When sorted by adhesion, risk VSMCs parsed into synthetic and contractile subpopulations, i.e., weakly adherent and strongly adherent, respectively. Of note, >90% of differentially expressed genes coregulated by haplotype and adhesion and were associated with Rho GTPases, i.e., contractility. Weakly adherent subpopulations expressed more short isoforms of ANRIL, and when overexpressed in knockout cells, ANRIL suppressed adhesion, contractility, and αSMA expression. These data suggest that variable lncRNA penetrance may drive mixed functional outcomes that confound pathology.

Abstract Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial–mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial–mesenchymal transition (EMT), partial EMT, and mesenchymal–epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor‐β, Wnt/β‐catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune‐related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP‐driven tumor deterioration. Additionally, we explore the potential technique for EMP‐based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP.

This document is an editorial published in Frontiers in Immunology titled "Targeting regulatory cells in cancer: old and new approaches in immunotherapy." The editorial discusses the role of regulatory cells in the tumor microenvironment (TME) and their impact on cancer progression and response to treatment. It highlights the potential of targeting regulatory cells as a therapeutic strategy to overcome immunosuppression in malignancies and improve the efficacy of existing immunotherapies. The editorial also mentions several articles included in a research topic on this subject, covering recent advances and novel approaches in targeting regulatory cells in cancer. [Extracted from the article]

In the human body, the 1013 blood endothelial cells (ECs) which cover a surface of 500–700 m2 (Mai et al., 2013) are key players of tissue homeostasis, remodeling and regeneration. Blood vessel ECs play a major role in the regulation of metabolic and gaz exchanges, cell trafficking, blood coagulation, vascular tone, blood flow and fluid extravasation (also referred to as blood vascular permeability). ECs are heterogeneous in various capillary beds and have the exquisite capacity to cope with environmental changes by regulating their gene expression. Ischemia has major detrimental effects on the endothelium and ischemia-induced regulation of vascular integrity is of paramount importance for human health, as small amounts of fluid accumulation in the interstitium may be responsible for major effects on organ functions and patients outcome. In this review, we will here focus on the stimuli and the molecular mechanisms that control blood endothelium maintenance and phenotypic plasticity/transition involved in controlling blood capillary leakage that might open new avenues for therapeutic applications. [ABSTRACT FROM AUTHOR]

Deep and comprehensive molecular analyses have started to pinpoint the genetic and epigenetic differences between α- and β-cells that could underlie the mechanisms defining their identity. The α-cell transcriptome is altered under different diabetic conditions, resulting in decreased expression of some α-cell-enriched genes alongside increased expression of some β-cell-enriched genes, but without reprogramming into insulin (INS)+ cells or activation of other key β-cell-specific genes. Multiple genetic and chemical methods have been used to reprogram mouse α-cells into INS-secreting cells in vivo , highlighting a difference in plasticity between embryonic and adult α-cells. Human α-cells have also been reprogrammed in vitro using PDX1 plus MAFA overexpression into INS-secreting cells that have reduced immunogenicity. Systematic molecular dissection of the mechanisms controlling α-cell reprogramming using an array of different in vitro and in vivo techniques will be necessary to develop efficient diabetes therapies. β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity. [ABSTRACT FROM AUTHOR]

Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer. [ABSTRACT FROM AUTHOR]

The metastasis is a multistep process in which a small proportion of cancer cells are detached from the colony to enter into blood cells for obtaining a new place for metastasis and proliferation. The metastasis and cell plasticity are considered major causes of cancer-related deaths since they improve the malignancy of cancer cells and provide poor prognosis for patients. Furthermore, enhancement in the aggressiveness of cancer cells has been related to the development of drug resistance. Metastasis of pancreatic cancer (PC) cells has been considered one of the major causes of death in patients and their undesirable prognosis. PC is among the most malignant tumors of the gastrointestinal tract and in addition to lifestyle, smoking, and other factors, genomic changes play a key role in its progression. The stimulation of EMT in PC cells occurs as a result of changes in molecular interaction, and in addition to increasing metastasis, EMT participates in the development of chemoresistance. The epithelial, mesenchymal, and acinar cell plasticity can occur and determines the progression of PC. The major molecular pathways including STAT3, PTEN, PI3K/Akt, and Wnt participate in regulating the metastasis of PC cells. The communication in tumor microenvironment can provide by exosomes in determining PC metastasis. The components of tumor microenvironment including macrophages, neutrophils, and cancer-associated fibroblasts can modulate PC progression and the response of cancer cells to chemotherapy. [ABSTRACT FROM AUTHOR]

The search for new therapeutic strategies against cancer has favored the emergence of rationally designed treatments. These treatments have focused on attacking cell plasticity mechanisms to block the transformation of epithelial cells into cancerous cells. The aim of these approaches was to control particularly lethal cancers such as hepatocellular carcinoma. However, they have not been able to control the progression of cancer for unknown reasons. Facing this scenario, emerging areas such as systems biology propose using engineering principles to design and optimize cancer treatments. Beyond the possibilities that this approach might offer, it is necessary to know whether its implementation at a clinical level is viable or not. Therefore, in this paper, we will review the engineering principles that could be applied to rationally design strategies against hepatocellular carcinoma, and discuss whether the necessary elements exist to implement them. In particular, we will emphasize whether these engineering principles could be applied to fight hepatocellular carcinoma.

Cell membrane surface tension has emerged as a pivotal biophysical factor governing cell behavior and fate. This review systematically delineates recent advances in techniques for cell membrane surface tension quantification, mechanosensing mechanisms, and regulatory roles of cell membrane surface tension in modulating major cellular processes. Micropipette aspiration, tether pulling, and newly developed fluorescent probes enable the measurement of cell membrane surface tension with spatiotemporal precision. Cells perceive cell membrane surface tension via conduits including mechanosensitive ion channels, curvature-sensing proteins (e.g. BAR domain proteins), and cortex-membrane attachment proteins (e.g. ERM proteins). Through membrane receptors like integrins, cells convert mechanical cues into biochemical signals. This conversion triggers cytoskeletal remodeling and extracellular matrix interactions in response to environmental changes. Elevated cell membrane surface tension suppresses cell spreading, migration, and endocytosis while facilitating exocytosis. Moreover, reduced cell membrane surface tension promotes embryonic stem cell differentiation and cancer cell invasion, underscoring cell membrane surface tension as a regulator of cell plasticity. Outstanding questions remain regarding cell membrane surface tension regulatory mechanisms and roles in tissue development/disease in vivo. Emerging tools to manipulate cell membrane surface tension with high spatiotemporal control in combination with omics approaches will facilitate the elucidation of cell membrane surface tension-mediated effects on signaling networks across various cell types/states. This will accelerate the development of cell membrane surface tension-based biomarkers and therapeutics for regenerative medicine and cancer. Overall, this review provides critical insights into cell membrane surface tension as a potent orchestrator of cell function, with broader impacts across mechanobiology.

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.

Prostate cancer is the second leading cause of death in men. A challenge in treating prostate cancer is overcoming cell plasticity, which links cell phenotype changes and chemoresistance. In this work, a microfluidic device coupled with electrical impedance spectroscopy (EIS), an electrode-based cell characterization technique, was used to study the electrical characteristics of phenotype changes for (1) prostate cancer cell lines (PC3, DU145, and LNCaP cells), (2) cells grown in 2D monolayer and 3D suspension cell culture conditions, and (3) cells in the presence (or absence) of the anti-cancer drug nigericin. To validate observations of phenotypic change, we measured the gene expression of two epithelial markers, E-cadherin (CDH1) and Tight Junction Protein 1 (ZO-1). Our results showed that PC3, DU145, and LNCaP cells were discernible with EIS. Secondly, moderate phenotype changes based on differences in cell culture conditions were detected with EIS and supported by the gene expression of CDH1. Lastly, we showed that EIS can detect chemoresistant-related cell phenotypes with nigericin drug treatment. EIS is a promising label-free tool for detecting cell phenotype changes associated with chemoresistance. Further development will enable the detection and characterization of many other types of cancer cells. [ABSTRACT FROM AUTHOR]

Plastic deformation in cells and tissues has been found to play crucial roles in collective cell migration, cancer metastasis, and morphogenesis. However, the fundamental question of how plasticity is initiated in individual cells and then propagates within the tissue remains elusive. Here, we develop a mechanism-based theory of cellular and tissue plasticity that accounts for all key processes involved, including the activation and development of active contraction at different scales as well as the formation of endocytic vesicles on cell junctions and show that this theory achieves quantitative agreement with all existing experiments. Specifically, it reveals that, in response to optical or mechanical stimuli, the myosin contraction and thermal fluctuation-assisted formation and pinching of endocytic vesicles could lead to permanent shortening of cell junctions and that such plastic constriction can stretch neighboring cells and trigger their active contraction through mechanochemical feedbacks and eventually their plastic deformations as well. Our theory predicts that endocytic vesicles with a size around 1 to 2 µm will most likely be formed and a higher irreversible shortening of cell junctions could be achieved if a long stimulation is split into multiple short ones, all in quantitative agreement with experiments. Our analysis also shows that constriction of cells in tissue can undergo elastic/unratcheted to plastic/ratcheted transition as the magnitude and duration of active contraction increases, ultimately resulting in the propagation of plastic deformation waves within the monolayer with a constant speed which again is consistent with experimental observations. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review aims to summarize (i) the latest evidence on cranial neural crest cells (CNCC) contribution to craniofacial development and ossification; (ii) the recent discoveries on the mechanisms responsible for their plasticity; and (iii) the newest procedures to ameliorate maxillofacial tissue repair. Recent Findings: CNCC display a remarkable differentiation potential that exceeds the capacity of their germ layer of origin. The mechanisms by which they expand their plasticity was recently described. Their ability to participate to craniofacial bone development and regeneration open new perspectives for treatments of traumatic craniofacial injuries or congenital syndromes. Summary: These conditions can be life-threatening, require invasive maxillofacial surgery and can leave deep sequels on our health or quality of life. With accumulating evidence showing how CNCC-derived stem cells potential can ameliorate craniofacial reconstruction and tissue repair, we believe a deeper understanding of the mechanisms regulating CNCC plasticity is essential to ameliorate endogenous regeneration and improve tissue repair therapies. [ABSTRACT FROM AUTHOR]

Abstract With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. It is curable if diagnosed at earlier stages but can become life-threateningly malignant if not treated timely. With no racial or gender predisposition, or even environmental factors known to have been involved in the incidence of the disease, retinoblastoma is often considered a clinical success story in pediatric oncology. The survival rate in highly developed countries is higher than 95% and they have achieved this because of the advancement in the development of diagnostics and treatment techniques. This includes developing the already existing techniques like chemotherapy and embarking on new strategies like enucleation, thermotherapy, cryotherapy, etc. Early diagnosis, studies on the etiopathogenesis and genetics of the disease are the need of the hour for improving the survival rates. According to the Knudson hypothesis, also known as the two hit hypothesis, two hits on the retinoblastoma susceptibility (RB) gene is often considered as the initiating event in the development of the disease. Studies on the molecular basis of the disease have also led to deciphering the downstream events and thus in the discovery of biomarkers and related targeted therapies. Furthermore, improvements in molecular biology techniques enhanced the development of efficient methods for early diagnosis, genetic counseling, and prevention of the disease. In this review, we discuss the genetic and molecular features of retinoblastoma with a special emphasis on the mutation leading to the dysregulation of key signaling pathways involved in cell proliferation, DNA repair, and cellular plasticity. Also, we describe the classification, clinical and epidemiological relevance of the disease, with an emphasis on both the traditional and innovative treatments to tackle retinoblastoma. Video Abstract

Plasticity in plant architecture drives plant performance through dedicated molecular networks.

Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.

Tissue resident stem cells are capable of remarkable plasticity in areas of tissue damage, where inflammatory cells accumulate as part of the reparative response. A study in the lung now provides critical insight on how inflammatory signals alter cell-to-cell Notch signaling within the airway niche to drive stem cell plasticity.

Cartilage damage affects millions of people worldwide. Tissue engineering strategies hold the promise to provide off‐the‐shelf cartilage analogs for tissue transplantation in cartilage repair. However, current strategies hardly generate sufficient grafts, as tissues cannot maintain size growth and cartilaginous phenotypes simultaneously. Herein, a step‐wise strategy is developed for fabricating expandable human macromass cartilage (macro‐cartilage) in a 3D condition by employing human polydactyly chondrocytes and a screen‐defined serum‐free customized culture (CC). CC‐induced chondrocytes demonstrate improved cell plasticity, expressing chondrogenic biomarkers after a 14.59‐times expansion. Crucially, CC‐chondrocytes form large‐size cartilage tissues with average diameters of 3.25 ± 0.05 mm, exhibiting abundant homogenous matrix and intact structure without a necrotic core. Compared with typical culture, the cell yield in CC increases 2.57 times, and the expression of cartilage marker collagen type II increases 4.70 times. Transcriptomics reveal that this step‐wise culture drives a proliferation‐to‐differentiation process through an intermediate plastic stage, and CC‐chondrocytes undergo a chondral lineage‐specific differentiation with an activated metabolism. Animal studies show that CC macro‐cartilage maintains a hyaline‐like cartilage phenotype in vivo and significantly promotes the healing of large cartilage defects. Overall, an efficient expansion of human macro‐cartilage with superior regenerative plasticity is achieved, providing a promising strategy for joint regeneration. [ABSTRACT FROM AUTHOR]

With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. It is curable if diagnosed at earlier stages but can become life-threateningly malignant if not treated timely. With no racial or gender predisposition, or even environmental factors known to have been involved in the incidence of the disease, retinoblastoma is often considered a clinical success story in pediatric oncology. The survival rate in highly developed countries is higher than 95% and they have achieved this because of the advancement in the development of diagnostics and treatment techniques. This includes developing the already existing techniques like chemotherapy and embarking on new strategies like enucleation, thermotherapy, cryotherapy, etc. Early diagnosis, studies on the etiopathogenesis and genetics of the disease are the need of the hour for improving the survival rates. According to the Knudson hypothesis, also known as the two hit hypothesis, two hits on the retinoblastoma susceptibility (RB) gene is often considered as the initiating event in the development of the disease. Studies on the molecular basis of the disease have also led to deciphering the downstream events and thus in the discovery of biomarkers and related targeted therapies. Furthermore, improvements in molecular biology techniques enhanced the development of efficient methods for early diagnosis, genetic counseling, and prevention of the disease. In this review, we discuss the genetic and molecular features of retinoblastoma with a special emphasis on the mutation leading to the dysregulation of key signaling pathways involved in cell proliferation, DNA repair, and cellular plasticity. Also, we describe the classification, clinical and epidemiological relevance of the disease, with an emphasis on both the traditional and innovative treatments to tackle retinoblastoma. -y-wSoSY3DLWKHAp-w4afq Video Abstract [ABSTRACT FROM AUTHOR]

Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood. HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro , CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair. [Display omitted] • Hepatobiliary cells are associated with poor outcomes in patients with ArLD. • Hepatobiliary cells express pathways related to inflammation and stemness. • Cxcr4 drives hepatocyte dedifferentiation in chronic liver injury. • Cxcr4 overexpression in hepatocytes promotes hepatocyte dedifferentiation and injury progression. • Genetic deletion or pharmacological inhibition of Cxcr4 reverts hepatocyte dedifferentiation. [ABSTRACT FROM AUTHOR]

Hitherto, calcified aortic valves (AVs) and failing bioprosthetic heart valves (BHVs) have been investigated by similar approaches, mostly limited to various immunostaining techniques. Having employed multiple immunostaining combinations, we demonstrated that AVs retain a well-defined cellular hierarchy even at severe stenosis, whilst BHVs were notable for the stochastic degradation of the extracellular matrix (ECM) and aggressive infiltration by ECM-digesting macrophages. Leukocytes (CD45+) comprised ≤10% cells in the AVs but were the predominant cell lineage in BHVs (≥80% cells). Albeit cells with uncertain immunophenotype were rarely encountered in the AVs (≤5% cells), they were commonly found in BHVs (≥80% cells). Whilst cell conversions in the AVs were limited to the endothelial-to-mesenchymal transition (represented by CD31+α-SMA+ cells) and the formation of endothelial-like (CD31+CD68+) cells at the AV surface, BHVs harboured numerous macrophages with a transitional phenotype, mostly CD45+CD31+, CD45+α-SMA+, and CD68+α-SMA+. In contrast to immunostaining, which was unable to predict cell function in the BHVs, our whole-specimen, nondestructive electron microscopy approach (EM-BSEM) was able to distinguish between quiescent and matrix-degrading macrophages, foam cells, and multinucleated giant cells to conduct the ultrastructural analysis of organelles and the ECM, and to preserve tissue integrity. Hence, we suggest EM-BSEM as a technique of choice for studying the cellular landscape of BHVs. [ABSTRACT FROM AUTHOR]

Fibroblasts are the major cell population of connective tissue, including the skin dermis, and are best known for their function in depositing and remodelling the extracellular matrix. Besides their role in extracellular matrix homeostasis, fibroblasts have emerged as key players in many biological processes ranging from tissue immunity and wound healing to hair follicle development. Recent advances in single‐cell RNA‐sequencing technologies have revealed an astonishing transcriptional fibroblast heterogeneity in the skin and other organs. A key challenge in the field is to understand the functional relevance and significance of the identified new cell clusters in health and disease. Here, we discuss the functionally distinct fibroblast subtypes identified in skin homeostasis and repair and how they evolve in fibrotic disease conditions, in particular keloid scars and cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Renin cells are precursors for other cell types in the kidney and show high plasticity in postnatal life in response to challenges to homeostasis. Our previous single-cell RNA-sequencing studies revealed that the dual zinc-finger transcription factor Gata3, which is important for cell lineage commitment and differentiation, is expressed in mouse renin cells under normal conditions and homeostatic threats. We identified a potential Gata3-binding site upstream of the renin gene leading us to hypothesize that Gata3 is essential for renin cell identity. We studied adult mice with conditional deletion of Gata3 in renin cells: Gata3fl/fl;Ren1dCre/+ (Gata3-cKO) and control Gata3fl/fl;Ren1d+/+ counterparts. Gata3 immunostaining revealed that Gata3-cKO mice had significantly reduced Gata3 expression in juxtaglomerular, mesangial, and smooth muscle cells, indicating a high degree of deletion of Gata3 in renin lineage cells. Gata3-cKO mice exhibited a significant increase in blood urea nitrogen, suggesting hypovolemia and/or compromised renal function. By immunostaining, renin-expressing cells appeared very thin compared with their normal plump shape in control mice. Renin cells were ectopically localized to Bowman’s capsule in some glomeruli, and there was aberrant expression of actin-α2 signals in the mesangium, interstitium, and Bowman’s capsule in Gata3-cKO mice. Distal tubules showed dilated morphology with visible intraluminal casts. Under physiological threat, Gata3-cKO mice exhibited a lower increase in mRNA levels than controls. Hematoxylin-eosin, periodic acid-Schiff, and Masson’s trichrome staining showed increased glomerular fusion, absent cubical epithelial cells in Bowman’s capsule, intraglomerular aneurysms, and tubular dilation. In conclusion, our results indicate that Gata3 is crucial to the identity of cells of the renin lineage. NEW & NOTEWORTHY Gata3, a dual zinc-finger transcription factor, is responsible for the identity and localization of renin cells in the kidney. Mice with a conditional deletion of Gata3 in renin lineage cells have abnormal kidneys with juxtaglomerular cells that lose their characteristic location and are misplaced outside and around arterioles and glomeruli. The fundamental role of Gata3 in renin cell development offers a new model to understand how transcription factors control cell location, function, and pathology. [ABSTRACT FROM AUTHOR]

The advent of sequencing technologies for assessing chromosome conformations has provided a wealth of information on the organization of the 3-dimensional genome and its role in cancer progression. It is now known that changes in chromatin folding and accessibility can promote aberrant activation or repression of transcriptional programs that can drive tumorigenesis and progression in diverse cancers. This includes breast cancer, which comprises several distinct subtypes defined by their unique transcriptomes that dictate treatment response and patient outcomes. Of these, basal-like breast cancer is an aggressive subtype controlled by a pluripotency-enforcing transcriptome. Meanwhile, the more differentiated luminal subtype of breast cancer is driven by an estrogen receptor-dominated transcriptome that underlies its responsiveness to antihormone therapies and conveys improved patient outcomes. Despite the clear differences in molecular signatures, the genesis of each subtype from normal mammary epithelial cells remains unclear. Recent technical advances have revealed key distinctions in chromatin folding and organization between subtypes that could underlie their transcriptomic and, hence, phenotypic differences. These studies also suggest that proteins controlling particular chromatin states may be useful targets for treating aggressive disease. In this review, we explore the current state of understanding of chromatin architecture in breast cancer subtypes and its potential role in defining their phenotypic characteristics. [ABSTRACT FROM AUTHOR]

Cellular plasticity defines the capacity of cells to adopt distinct identities during development, tissue homeostasis and regeneration. Dynamic fluctuations between different states, within or across lineages, are regulated by changes in chromatin accessibility and in gene expression. When deregulated, cellular plasticity can contribute to cancer initiation and progression. Cancer cells are remarkably plastic which contributes to phenotypic and functional heterogeneity within tumours as well as resistance to targeted therapies. It is for these reasons that the scientific community has become increasingly interested in understanding the molecular mechanisms governing cancer cell plasticity. The purpose of this mini-review is to discuss different examples of cellular plasticity associated with metaplasia and epithelial-mesenchymal transition with a focus on therapy resistance.

Monocytes are crucial regulators of inflammation, and are characterized by three distinct subsets in humans, of which classical and non-classical are the most abundant. Different subsets carry out different functions and have been previously associated with multiple inflammatory conditions. Dissecting the contribution of different monocyte subsets to disease is currently limited by samples and cohorts, often resulting in underpowered studies and poor reproducibility. Publicly available transcriptome profiles provide an alternative source of data characterized by high statistical power and real-world heterogeneity. However, most transcriptome datasets profile bulk blood or tissue samples, requiring the use of in silico approaches to quantify changes in cell levels. Here, we integrated 853 publicly available microarray expression profiles of sorted human monocyte subsets from 45 independent studies to identify robust and parsimonious gene expression signatures, consisting of 10 genes specific to each subset. These signatures maintain their accuracy regardless of disease state in an independent cohort profiled by RNA-sequencing and are specific to their respective subset when compared to other immune cells from both myeloid and lymphoid lineages profiled across 6160 transcriptome profiles. Consequently, we show that these signatures can be used to quantify changes in monocyte subsets levels in expression profiles from patients in clinical trials. Finally, we show that proteins encoded by our signature genes can be used in cytometry-based assays to specifically sort monocyte subsets. Our results demonstrate the robustness, versatility, and utility of our computational approach and provide a framework for the discovery of new cellular markers.

During development and in several diseases, endothelial cells (EC) can undergo complete endothelial-to-mesenchymal transition (EndoMT or EndMT) to generate endothelial-derived mesenchymal cells. Emerging evidence suggests that ECs can also undergo a partial EndoMT to generate cells with intermediate endothelial- and mesenchymal-character. This partial EndoMT event is transient, reversible, and supports both developmental and pathological angiogenesis. Here, we discuss possible regulatory mechanisms that may control the EndoMT program to dictate whether cells undergo complete or partial mesenchymal transition, and we further consider how these pathways might be targeted therapeutically in cancer.

Abstract Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.

Cell plasticity is important in development and tissue remodeling. Cells can sense physical and chemical cues from their local microenvironment and transduce the signals into the nucleus to regulate the epigenetic state and gene expression, resulting in a change in cell phenotype. In this review, we highlight the role of mechanical cues in regulating stem cell differentiation and cell reprogramming through the modulation of histone modifications. The effects of various mechanical cues, including matrix stiffness, mechanical stretch, and shear stress, on cell fate during tissue regeneration and remodeling will be discussed. Taken together, recent work demonstrates that the alterations in histone modifications by mechanical stimuli can facilitate epigenetic changes during cell phenotypic switching, which has potential applications in the development of biomaterials and bioreactors for cell engineering.

Abstract Cartilage damage affects millions of people worldwide. Tissue engineering strategies hold the promise to provide off‐the‐shelf cartilage analogs for tissue transplantation in cartilage repair. However, current strategies hardly generate sufficient grafts, as tissues cannot maintain size growth and cartilaginous phenotypes simultaneously. Herein, a step‐wise strategy is developed for fabricating expandable human macromass cartilage (macro‐cartilage) in a 3D condition by employing human polydactyly chondrocytes and a screen‐defined serum‐free customized culture (CC). CC‐induced chondrocytes demonstrate improved cell plasticity, expressing chondrogenic biomarkers after a 14.59‐times expansion. Crucially, CC‐chondrocytes form large‐size cartilage tissues with average diameters of 3.25 ± 0.05 mm, exhibiting abundant homogenous matrix and intact structure without a necrotic core. Compared with typical culture, the cell yield in CC increases 2.57 times, and the expression of cartilage marker collagen type II increases 4.70 times. Transcriptomics reveal that this step‐wise culture drives a proliferation‐to‐differentiation process through an intermediate plastic stage, and CC‐chondrocytes undergo a chondral lineage‐specific differentiation with an activated metabolism. Animal studies show that CC macro‐cartilage maintains a hyaline‐like cartilage phenotype in vivo and significantly promotes the healing of large cartilage defects. Overall, an efficient expansion of human macro‐cartilage with superior regenerative plasticity is achieved, providing a promising strategy for joint regeneration.

In this perspective article, a clinically inspired phenotype-driven experimental approach is put forward to address the challenge of the adaptive response of solid cancers to small-molecule targeted therapies. A list of conditions is derived, including an experimental quantitative assessment of cell plasticity and an information theory-based detection of in vivo dependencies, for the discovery of post-transcriptional druggable mechanisms capable of preventing at multiple levels the emergence of plastic dedifferentiated slow-proliferating cells. The approach is illustrated by the author's own work in the example case of the adaptive response of BRAFV600-melanoma to BRAF inhibition. A bench-to-bedside and back to bench effort leads to a therapeutic strategy in which the inhibition of the baseline activity of the interferon-γ-activated inhibitor of translation (GAIT) complex, incriminated in the expression insufficiency of the RNA-binding protein HuR in a minority of cells, results in the suppression of the plastic, intermittently slow-proliferating cells involved in the adaptive response. A similar approach is recommended for the validation of other classes of mechanisms that we seek to modulate to overcome this complex challenge of modern cancer therapy.

Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness. [ABSTRACT FROM AUTHOR]

Single cell technologies, lineage tracing mouse models and advanced imaging techniques unequivocally improved the resolution of the cellular landscape of atherosclerosis. Although the discovery of the heterogeneous nature of the cellular plaque architecture has undoubtedly improved our understanding of the specific cellular states in atherosclerosis progression, it also adds more complexity to current and future research and will change how we approach future drug development. In this review, we will discuss how the revolution of new single cell technologies allowed us to map the cellular networks in the plaque, but we will also address current (technological) limitations that confine us to identify the cellular drivers of the disease and to pinpoint a specific cell state, cell subset or cell surface antigen as new candidate drug target for atherosclerosis. [Display omitted] • Single cell omics unveiled the heterogeneous cellular landscape of atherosclerosis. • Intraplaque heterogeneity adds complexity to current and future (drug) research. • Studying cell activation and cell-cell interactions is the next step forward. • More disease and site-specific therapies for atherosclerosis are needed. [ABSTRACT FROM AUTHOR]

In multicellular organisms, interactions between cells and intercellular communications form the very basis of the organism's survival, the functioning of its systems, the maintenance of homeostasis and adequate response to the environment. The accumulated experimental data point to the particular importance of intercellular communications in determining the fate of cells, as well as their differentiation and plasticity. For a long time, it was believed that the properties and behavior of cells were primarily governed by the interactions of secreted or membrane-bound ligands with corresponding receptors, as well as direct intercellular adhesion contacts. In this review, we describe various types of other, non-classical intercellular interactions and communications that have recently come into the limelight—in particular, the broad repertoire of extracellular vesicles and membrane protrusions. These communications are mediated by large macromolecular structural and functional ensembles, and we explore here the mechanisms underlying their formation and present current data that reveal their roles in multiple biological processes. The effects mediated by these new types of intercellular communications in normal and pathological states, as well as therapeutic applications, are also discussed. The in-depth study of novel intercellular interaction mechanisms is required for the establishment of effective approaches for the control and modification of cell properties both for basic research and the development of radically new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.

The pool of beta cell-specific CD8+ T cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell 'multipotency index' and found that beta cell-specific CD8+ T cells retained a stem-like epigenetic multipotency score. Single-cell assay for transposase-accessible chromatin using sequencing confirmed the coexistence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8+ T cells. Assessment of beta cell-specific CD8+ T cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8+ T cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8+ T cell responses and document the use of this methylation-based multipotency index for investigating human and mouse CD8+ T cell differentiation.

Background & aimsPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that invades surrounding structures and metastasizes rapidly. Although inflammation is associated with tumor formation and progression, little is known about the mechanisms of this connection. We investigate the effects of interleukin (IL) 22 in the development of pancreatic tumors in mice.MethodsWe performed studies with Pdx1-Cre;LSL-KrasG12D;Trp53+/-;Rosa26EYFP/+ (PKCY) mice, which develop pancreatic tumors, and PKCY mice with disruption of IL22 (PKCY Il22-/-mice). Pancreata were collected at different stages of tumor development and analyzed by immunohistochemistry, immunoblotting, real-time polymerase chain reaction, and flow cytometry. Some mice were given cerulean to induce pancreatitis. Pancreatic cancer cell lines (PD2560) were orthotopically injected into C57BL/6 mice or Il22-/-mice, and tumor development was monitored. Pancreatic cells were injected into the tail veins of mice, and lung metastases were quantified. Acini were collected from C57BL/6 mice and resected human pancreata and were cultured. Cell lines and acini cultures were incubated with IL22 and pharmacologic inhibitors, and protein levels were knocked down with small hairpin RNAs. We performed immunohistochemical analyses of 26 PDACs and 5 nonneoplastic pancreas specimens.ResultsWe observed increased expression of IL22 and the IL22 receptor (IL22R) in the pancreas compared with other tissues in mice; IL22 increased with pancreatitis and tumorigenesis. Flow cytometry indicated that the IL22 was produced primarily by T-helper 22 cells. PKCY Il22-/-mice did not develop precancerous lesions or pancreatic tumors. The addition of IL22 to cultured acinar cells increased their expression of markers of ductal metaplasia; these effects of IL22 were prevented with inhibitors of Janus kinase signaling to signal transducer and activator of transcription (STAT) (ruxolitinib) or mitogen-activated protein kinase kinase (MEK) (trametinib) and with STAT3 knockdown. Pancreatic cells injected into Il22-/- mice formed smaller tumors than those injected into C57BL/6. Incubation of IL22R-expressing PDAC cells with IL22 promoted spheroid formation and invasive activity, resulting in increased expression of stem-associated transcription factors (GATA4, SOX2, SOX17, and NANOG), and increased markers of the epithelial-mesenchymal transition (CDH1, SNAI2, TWIST1, and beta catenin); ruxolitinib blocked these effects. Human PDAC tissues had higher levels of IL22, phosphorylated STAT3, and markers of the epithelial-mesenchymal transition than nonneoplastic tissues. An increased level of STAT3 in IL22R-positive cells was associated with shorter survival times of patients.ConclusionsWe found levels of IL22 to be increased during pancreatitis and pancreatic tumor development and to be required for tumor development and progression in mice. IL22 promotes acinar to ductal metaplasia, stem cell features, and increased expression of markers of the epithelial-mesenchymal transition; inhibitors of STAT3 block these effects. Increased expression of IL22 by PDACs is associated with reduced survival times.