Gastric cancer remains a leading cause of cancer-related mortality worldwide, and effective preventive or therapeutic vaccines are still lacking. WNT1‑inducible signalling pathway protein 1 (WISP1/CCN4) is a secreted matricellular protein that is overexpressed in gastric tumours and associated with poor prognosis, making it a promising immunotherapy target. We aimed to design a multi‑epitope protein vaccine candidate targeting WISP1 using an immunoinformatics workflow. We predicted linear B‑cell epitopes from WISP1 and filtered them for antigenicity, non-allergenicity, and non-toxicity. High‑scoring MHC class I and class II T‑cell epitopes with broad HLA coverage were then selected. The final construct combined validated B‑ and T‑cell epitopes with appropriate linkers and a TLR‑agonist adjuvant to enhance immunogenicity. Physicochemical profiling indicated that the construct is stable, soluble, hydrophilic and antigenic, with no predicted allergenicity or toxicity. Secondary and tertiary structures were modelled, refined and validated, revealing proper folding and favourable stereochemical quality. Molecular docking showed strong binding to innate immune receptors, particularly TLR4, and molecular dynamics simulations confirmed stable receptor-vaccine interactions with low structural deviation. Binding‑free energy analysis further supported these results. Immune simulations predicted robust primary and secondary immune responses characterised by sustained IgG/IgM production, increased IFN‑γ and IL‑2, and activation of memory B and T cells. Codon optimisation and in‑silico cloning suggested feasibility for experimental expression. These results indicate that the proposed WISP1 multi‑epitope vaccine is antigenic, safe, structurally stable and capable of eliciting broad humoral and cellular immune responses in silico. This work provides a testable candidate for experimental validation and highlights secreted CCN family proteins as novel targets for gastric cancer vaccines.

Abstract Background/Aims Activated fibroblasts, called myofibroblasts, are responsible for the fibrosis seen in scleroderma. How to block myofibroblast activation and activity in scleroderma is unknown, but CCN3, a member of the CCN family of matricellular proteins, is anti-fibrotic and counteracts the profibrotic activity of the related protein CCN2. We have identified BLR-200 as a CCN3-derived peptide that retains CCN3’s antifibrotic properties in bleomycin-induced skin fibrosis. However, if CCN3’s and BLR-200’s antifibrotic properties translate to scleroderma patients is unknown. Methods To test the hypothesis that reduced CCN3 levels may exist in scleroderma patients, we used ELISAs to detect the amount of CCN2 and CCN3 in serum of healthy controls, early-onset diffuse (<24 months duration) scleroderma patients and those of later (>5 years) duration. To identify the fibroblast populations whose activation by bleomycin is suppressed by BLR-200, we conducted scRNAseq analysis of fibroblasts labelled postnatally with green fluorescent protein using mTmG mice, subjected or not to bleomycin-induced skin fibrosis in the presence or absence of BLR-200, that expressed a tamoxifen-dependent cre recombinase expressed under the control of a universal fibroblast-specific promoter/enhancer. Results CCN2 and CCN3 serum levels correlated well among healthy volunteers (controls) (r2=0.39, p < 0.03, N = 20), whereas scleroderma patients of < 2 years and of > 5 years duration showed patient-specific dysregulation of CCN2 and CCN3 protein levels (r2=0.048 and r2=0.116, respectively, N = 20). CCN2 and CCN3 levels increased in serum with patients of early duration (p < 0.05 vs p < 0.0001, respectively); however, increases in CCN3, but not CCN2, levels were observed in patients with late duration (p < 0.001 vs ns, respectively). In mice subjected to bleomycin-induced skin fibrosis, lineage tracing and scRNA-seq analyses revealed that myofibroblasts are derived from Pi16+/Col15+ve “universal” fibroblasts (N = 6, p < 0.01). BLR-200 prevented myofibroblast differentiation of Pi16+/Col15+ve “universal” fibroblasts in response to bleomycin toward an engrailed-1/Col8A1-positive subset of “universal” fibroblasts, a pro-fibrotic cell type previously shown to specifically upregulated in skin derived from scleroderma patients with active disease. Conclusion Given what is known about the relative activities of CCN2 and CCN3 in vivo, it is likely that serum levels of CCN3 rise in scleroderma patients in the body’s attempt to suppress CCN2-dependent fibrosis. Why this dysregulation appears to be patient-specific is unclear and requires further investigation. BLR-200 specifically targets the prevention of formation of an engrailed-1/Col8A1-positive fibroblast subpopulation that is specifically upregulated in skin in scleroderma patients. Therefore, BLR-200 appears to be a novel anti-fibrotic agent of potential translational relevance, particularly to patients with low serum levels of CCN3. Disclosure A. Leask: None. R.J. Stratton: None. B.A. Abdi: None. Z.J. Kannan: None. J. Nguyen: None. B.L. Riser: Corporate appointments; CEO, BLR Bio, LLC.

Originally identified in the 1990s as an extracellular matrix (ECM) protein, Cellular Communication Network factor 3 (CCN3) was recognized as a member of a structurally related family of six proteins sharing a conserved tetramodular organization and broad regulatory functions in biological processes such as cell proliferation, attachment, migration, differentiation, wound healing, and angiogenesis, as well as in pathological conditions including fibrosis and tumorigenesis. Among these proteins, CCN3 rapidly emerged as the first tumor-suppressive member capable of negatively regulating cell growth in both normal and pathological contexts. A conceptual shift emerged following observations that, in addition to full-length CCN3 detected in the extracellular matrix, amino-truncated CCN3 proteoforms are targeted to the nucleus. In addition to physically interacting with the Rpb7 subunit of RNA polymerase II (Pol II), CCN3 binds to the promoter region of PAI-2 and exhibits transcriptional regulatory activity both in vitro and ex vivo. The dual localization and functional versatility of CCN3 led to the proposal that this protein may function as a "moonlighting" factor capable of integrating extracellular cues with nuclear transcriptional regulation. This conceptual framework, however, has remained relatively underexplored. The nuclear localization of other family members, together with the more recent observation that nuclear CCN6 physically interacts with RNA polymerase II, may extend this concept to the entire CCN protein family. By revisiting and integrating a substantial body of published data that has remained insufficiently acknowledged, this review aims to underscore the biological significance of CCN proteoforms in the nuclei of tumor cells. The demonstration of physical interactions between CCN3 and components of the central transcriptional machinery invites reconsideration of the prevailing ECM-centered view of CCN proteins and opens new perspectives on their biological roles.

Reptiles, as the earliest vertebrate group to fully adapt to terrestrial environments, have reproductive strategies that hold critical significance for understanding biological evolution and ecological adaptation. However, the mechanisms of oogenesis in reptiles, particularly in the endangered Chinese alligator (Alligator sinensis), remain poorly understood. Here we integrated transcriptomic and non-coding RNA analyses to elucidate stage-specific lncRNA/miRNA-mRNA regulatory networks during oogenesis. Gonadal tissue samples were collected at three critical developmental stages: 1-day post-hatching (AH), 15-day post-hatching (BH), and 90-day post-hatching (CH). RNA sequencing revealed 568 upregulated and 222 downregulated genes during the early proliferation phase (from AH period to BH period), and 667 upregulated and 241 downregulated genes during the maturation phase (from BH period to CH period). Additionally, we identified 1,194 lncRNAs and 1,808 miRNAs dynamically expressed across these stages. During early proliferation, cell cycle genes (CCN3 - CCN Family Member 3, CDC45 - Cell Division Cycle 45) and signaling pathways (WNT - Wingless-Type MMTV Integration Site Family, FGF - Fibroblast Growth Factor) dominated, while metabolic genes (ALDOB-Aldolase B, Fructose-Bisphosphate, FABP4 - Fatty Acid Binding Protein 4) were suppressed. In the maturation phase, meiosis-related genes (STAG3 - Stromal Antigen 3, SPO11- Sporulation Protein 11 Homolog) and germ cell-specific factors (DAZL - Deleted in Azoospermia-Like, NOBOX - Newborn Ovary Homeobox) were upregulated, accompanied by miRNA-mediated suppression of non-essential functions. This study provides the first comprehensive roadmap of non-coding RNA-mediated oogenesis in reptiles, offering insights for conservation strategies in endangered species.

Chronic systemic inflammation and autoimmunity are hallmarks of rheumatoid arthritis (RA), an inflammatory illness that progressively deteriorates joints, resulting in permanent disability. Monocyte adhesion and infiltration into synovial tissue are critical steps in RA progression. WISP-3 (referred to as CCN6) is a member of the CCN family and plays a role in regulating various developmental processes. However, the role of WISP-3 in monocyte adhesion and macrophage polarization in RA remains unknown. Our high-throughput cytokine array data indicate that WISP-3 induces CCL4 synthesis in RA synovial fibroblasts (RASFs), subsequently enhancing monocyte adhesion to the synovium. Result from the GEO database confirm that levels of WISP-3 and CCL4 are markedly higher in RA patients compared to healthy controls. We also elucidated a detailed mechanism by which WISP-3 increases CCL4 synthesis in RASFs and promotes monocyte adhesion to the synovium by reducing miR-6894-5p expression via the MEK and ERK pathways. Furthermore, WISP-3 augments M1 macrophage polarization in the RA microenvironment. Thus, the WISP-3/CCL4 axis may serve as a novel therapeutic goal for RA treatment.

Nab-paclitaxel inhibits angiogenesis via the CYR61/integrin αvβ3 Axis: Exosomal proteomics insights into breast cancer chemoprevention.

Neonatal lung injury remains a major cause of morbidity among preterm infants and is a leading antecedent of bronchopulmonary dysplasia (BPD), a condition characterized by arrested alveolar development, inflammation, and extracellular matrix (ECM) remodeling. Despite significant advances in neonatal care, the mechanisms governing lung repair and regeneration remain incompletely understood. Recent research highlights the crucial role of matricellular proteins that orchestrate cell signaling, differentiation, and tissue remodeling in modulating–epithelial responses to injury. Among these, the CCN (CYR61/CTGF/NOV) family of proteins has emerged as a pivotal regulator of epithelial mesenchymal communication, with diverse and context-dependent functions in development, fibrosis, and regeneration.This review examines the distinct role of CCN5 (WISP2) within this family as a modulator of alveolar epithelial cell (AEC) plasticity in neonatal lung injury. We integrate findings from our own work with recent advances in CCN biology to elucidate how CCN5 influences epithelial survival, epithelial–mesenchymal transition (EMT), mitochondrial homeostasis, and intercellular signaling in hyperoxic injury. The review also contrasts CCN5 with other CCN members implicated in fibrotic lung diseases and situates it within broader matricellular signaling networks. By defining how CCN5 mediates epithelial resilience and tissue homeostasis, we propose it as a potential therapeutic target for mitigating BPD and enhancing regenerative outcomes in premature infants.

Cellular communication network factor 1 (CCN1), also known as cysteine-rich angiogenic inducer 61 (CYR61), is a pivotal member of the CCN family, which comprises six secretory matricellular proteins. CCN1 exhibits multifaceted biological functions, including regulation of cell proliferation, differentiation, senescence, angiogenesis and tissue repair. Current evidence demonstrates that CCN1 activates intracellular signalling cascades by binding to receptors such as integrins and heparan sulphate proteoglycans (HSPGs), thereby mediating its biological effects. Furthermore, CCN1 plays critical roles in diverse pathological conditions, including cutaneous wound healing, skin ageing, psoriasis, diabetic ulcers and melanoma. This review delineates the interaction between CCN1 and the extracellular matrix (ECM), highlighting its capacity to mediate dermo-epidermal communication and maintain skin structural homeostasis. As a tunable molecular target, CCN1 holds significant potential for addressing cutaneous disorders and enhancing skin health. Despite extensive investigations into its roles in dermatological diseases (e.g., psoriasis, melanoma), applications in cosmetics and cosmeceuticals remain nascent. Consequently, this study aims to elucidate the mechanistic contributions of CCN1 to skin physiology and pathology, providing a strategic framework for its translational exploitation in dermatological therapeutics and cosmeceutical innovation.

The CCN family of proteins is comprised of six matricellular proteins known to regulate multiple cellular processes such as adhesion, proliferation, differentiation, and apoptosis. CCN proteins are known to function through the binding of integrin receptors and through the regulation of growth factors and cytokines in the context of cardiovascular and skeletal development, injury repair, fibrosis, inflammation and cancer. The expression and roles of several CCNs, particularly CCN1 and CCN2, have been investigated in the ovary as they are effectors of the Hippo signaling pathway, and their role in the development of ovarian fibrosis has been described. Here we review the patterns of expression of CCN1-6 in the ovarian follicle, and the role of CCN2 in follicle development and steroidogenesis, and the expression and potential actions of CCN1-6 in ovarian cancers. We highlight the roles CCNs may play in inflammatory processes, and put forth a case for CCN involvement in the process of ovulation.

PurposeThe aim of this study was to investigate the expression and clinical implications of CCN family member 5 (CCN5) and the oestrogen receptor (ER) in advanced breast cancer (BC).MethodsA total of 130 patients with advanced BC were selected for the study. Samples of normal breast tissue, ductal carcinoma in situ (DCIS), and invasive carcinoma were collected. The expression levels of CCN5 and ER in these tissues were examined using immunohistochemical methods. The correlation between expression of CCN5 and ER in different tissues and also differences in expression in invasive carcinoma were analysed. In addition, the relationship between CCN5 expression in advanced BC tissues and clinical pathological features was examined.ResultsCCN5 and ER had low expression in normal breast tissues and invasive carcinoma tissues, but high expression in DCIS, with this difference being statistically significant (X2 = 119.899, P < 0.001; X2 = 113.524, P < 0.001, respectively). The expression of CCN5 and ER in different tissues of patients with advanced BC showed a positive correlation. Significant differences were also observed in the positive and negative expression of CCN5 and ER (X2 = 56.358, P < 0.001). Moreover, the expression of CCN5 protein in advanced BC showed a statistically significant associations (P < 0.05) with the expression of the progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), Ki-67, and P53, tumor diameter, histological grade, lymph node metastasis, pathological molecular subtype, and clinical staging.ConclusionHigh expression of CCN5 and ER was observed in DCIS tissues of patients with advanced BC, with their expression being positively correlated. These findings suggest that CCN5 and ER may have a potential synergistic role in the progression of BC that influences the progression of advanced BC and can also be used to predict the effectiveness of endocrine therapy.

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a prominent extracellular matrix (ECM) deposition and poor prognosis. Cancer-associated fibroblasts (CAFs) actively remodel the ECM and can mediate immune suppression within the PDAC tumor microenvironment (TME). However, CAFs are highly heterogeneous and plastic components of the tumor ECM in PDAC. Previously, we discovered that a core inflammatory gene network (CIGN) associated with poor prognosis serves chemokine production in CAFs in PDAC. The CIGN is defined by two markers (DCBLD2 and PLAU). Subsequently, we focus on ascertaining whether CAFs under CIGN are associated with the current typical classification of CAFs, such as myofibroblastic CAFs and inflammatory CAFs. Method: Before this, we employed bulk RNA seq data of 183 PDAC patients from the Cancer Genome Altas based on 104 inflammatory gene sets from the Molecular Signatures Database to define the CIGN with poor prognosis. We also utilized three scRNA-seq series of PDAC patient tissues to analyze the impact of our CIGN on PDAC TME. Now, to better characterize CAFs in PDAC, CAFs were re-clustered into subclusters by performing the FindClusters function. We identified each cell cluster by comparing the cluster-specific genes to current typical CAF population signatures. Distinct patterns of CAF subclusters were discovered for CIGN positive and negative groups by t-distributed stochastic neighbor embedding. Furthermore, differentially expressed genes were acquired from CAFs under CIGN using differential expression analysis and Gene Ontology enrichment analysis Results: We discovered two CIGN marker genes (DCBLD2 and PLAU) were both found primarily expressed in CAFs, and significantly higher in CAFs of PDAC patients defined by the CIGN (CIGN CAFs) previously. In this study, we found CIGN CAFs tended to be more inflammatory, while non-CIGN CAFs were consisted of a large number of myofibroblastic subtype. The 289 up-regulated Differential Expression Genes (DEGs) from CIGN CAFs were enriched in processes related to connective tissue development, positive regulation of ERK1 and ERK2 cascade, positive regulation of MAPK cascade, positive regulation of JNK cascade, reactive oxygen species metabolic process, collagen-containing extracellular matrix, growth factor binding. CCN2 was the only one among 289 up-regulated DEGs involved in multiple functions of CIGN CAFs, such as biological process, cell component, and molecular function, including but not limited to those listed above. CCN2 (CTGF, connective tissue growth factor) is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. Conclusion: CAFs in PDAC patients defined by the CIGN exhibited inflammatory characteristics with high CCN2 expression. As abundant tumour-promoting cells in the ECM, CAFs are promising targets for novel anti-tumour interventions. Fundings: Hong Kong Theme-based Scheme (T12-201/20-R) Citation Format: Shuangying Qiao, Liu YANG, Ge ZHANG, Aiping LU, Fangfei LI. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma patients defined by a core inflammatory gene network exhibited inflammatory characteristics with high CCN2 expression [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B097.

ABSTRACTBackgroundThe presence of glioma stem cells (GSCs) and the occurrence of mesenchymal phenotype transition contribute to the miserable prognosis of glioblastoma (GBM). Cellular communication network factor 1 (CCN1) is upregulated within various malignancies and associated with cancer development and progression, while the implications of CCN1 in the phenotype transition and tumorigenicity of GSCs remain unclear.MethodsData for bioinformatic analysis were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. A range of primary GBM and GSC cell models were then used to demonstrate the regulatory role of CCN1 via the phenotype validation, tumor sphere formation assays, extreme limiting dilution assays (ELDA), and transwell assays. To screen out the downstream signaling pathway, we employed high‐throughput RNA‐seq. Intracranial xenograft GSC mouse models were used to investigate the role of CCN1 in vivo.ResultsAmong the CCN family members, CCN1 was highly expressed in MES‐GBM/GSCs and was correlated with a poor prognosis. Both in vitro and in vivo assays indicated that knockdown of CCN1 in MES‐GSCs reduced the tumor stemness, proliferation, invasion, and tumorigenicity, whereas CCN1 overexpression in PN‐GSCs exhibited the opposite effects. Mechanistically, CCN1 triggered the FAK/STAT3 signaling in autocrine and paracrine manners to upregulate the expression of S100A8. Knockdown of S100A8 inactivated NF‐κB/p65 pathway and significantly suppressed the tumorigenesis of MES‐GSCs.ConclusionOur findings reveal that CCN1 may be an important factor in the enhanced invasiveness and MES phenotype transition of GSCs and highlight the potential to target CCN1 for treating GBM.

The CCN family of proteins is composed of six members (CCN1-CCN6) sharing a tetra-modular organization and a striking conservation of their primary structure. The CCN acronym was originally assigned in 1993 by P. Bork to three newly discovered factors (originally called CTGF, CYR61, and NOV), which he proposed to constitute a new family of proteins on the basis of their common physical features. Six years later, three other proteins (Wisp1-3), sharing the same tetramodular organization, joined the family (figure 1). The HUGO-recognized acronyms for the CCN proteins were officialized in 2018[1]. The CCN family turned out to contain positive and negative regulators of cell proliferation and differentiation, with pro- and anti-tumorigenic activities. A significant amount of work has been performed to identify the participation of the constitutive modules in these biological features. The aim of this review is to briefly examine the potential roles assigned to the constitutive modules of CCN proteins and propose a critical view of the structural basis for their interactions and functions.

From June 20th to June 23rd, the 12th International workshop on the CCN Family of Genes has been held at the Scandic Holmenkollen Park Hotel, OSLO–Norway Organizers Professor Håvard Attramadal and Dr. Vivi T. Monsen, Oslo University Hospital Co-organizers Professor Bernard Perbal and Annick Perbal, International CCN Society, Nice France The workshop has been scientifically and socially very successful. Since the previous meeting held in Nice in 2022, it has been opened to different fields. This year, Dr. Katia Scotlandi from Bologna, Italy, has been selected to be the 9th ICCNS Awardee. Dr. Katia Scotlandi has long been committed to advancing research and scientific interest in the field of IGF and insulin system. Her scientific group has demonstrated the importance of the related signaling pathway in sarcomas, particularly in the Ewing sarcoma and participated in the development of rationale strategies to inhibit IGF1R-mediated signaling at preclinical level. She has also highlighted the role of the insulin receptor in the rapid development of resistance to antibodies targeting IGF1R. More recently, she has introduced the concept that the RNA-binding protein IGF2BP3 may regulate the cell sensitivity to anti-IGF1R agents. In addition she has significantly contributed hard to the identification of novel biomarkers of risk and prognosis, including CCN3, as well as of new therapeutic targets for these tumors. More recently, she has developed a platform for sequencing and establishment of complex preclinical models to accelerate our understanding of bone sarcomas. Listing of the ICCNS awardees Program Thursday, June 20 9:00 Registration begins 10:30–11:30 Business meeting for the JCCS Editorial Board. 11:45–13:00 Lunch Workshop Opening Session I ECM Proteins in Cell Communication and Signaling Chairs: Brahim Chaqour and Vivi T. Monsen 14:40–15:10 Coffee Break 18:30 Welcome reception and Dinner with Live Music at Scandic Holmenkollen Park Hotel Session II Vascular Development and Pathophysiology Chairs: Lester Lau and Håvard Attramadal 9:50–10:20 Coffee Break Session III Mechanisms of Diseases: Fibrosis and The Matrix Chairs: George Bou-Gharios and Satoshi Kubota Lunch 12:10–13:30 Boat Trip on the Oslo Fjord with dinner Saturday, June 22 Session IV Tissue Development and Homeostasis Chairs: Blandine Poulet and Bernard Perbal 9:45–10:15 Coffee Break Lunch 12:00-13:00 Session V Mechanisms of Disease: Cancer and the Matrix Chairs: Stephen Twigg and Ray Birge 14:05–14:30 Coffee Break Free evening Special JCCS Executive Board Meeting Sunday, June 23 Session VI Chair: Bernard Perbal 8:45–9:00 Bernard Perbal ICCNS Award Presentation Educational Lecture 10:20–10:45 Coffee Break 12:00 Lunch Departure of the participants

The mechanisms underlying the remarkable capacity of the liver to regenerate are still not completely understood. Particularly, the cross-talk between cytokines and cellular components of the process is of utmost importance because they represent potential avenues for diagnostics and therapeutics. WNT1-inducible-signaling pathway protein 1 (WISP1) is a cytokine member of the CCN family, a family of proteins that play many different roles in liver pathophysiology. WISP1 also belongs to the earliest and strongest upregulated genes in mouse livers after CCl4 intoxication and has recently been shown to be secreted by tumor cells and to bind to type 1 collagen to cause its linearization in vitro and in tumor tissue in vivo. We show that WISP1 expression is strongly induced by TGFβ, a critical cytokine in wound healing processes. Additionally, secretion of WISP1 protein by hepatic stellate is increased in cells upon TGFβ stimulation (~seven-fold increase). Furthermore, WISP1 facilitates the migration of mouse hepatic stellate cells through collagen in vitro. However, in WISP1 knockout mice, no difference in stellate cell accumulation in damaged liver tissue and no influence on fibrosis was obtained, probably because the knockout of WISP1 was compensated by other factors in vivo.

The 12th international workshop on the CCN family of genes took place at the Scandic Holmenkollen Park Hotel in Oslo, Norway from June 20-23, 2024. In 2024, it was the second time, following the Nice meeting in 2022, that the scientific topics were expanded to include additional cellular signaling and communication pathways of interest to the CCN Society members, as suggested by Bernard Perbal in 2019. The 12th international CCN workshop, organized by Håvard Attramadal and Vivi T. Monsen, along with co-organizers Bernard and Annick Perbal, was given the subtitle "Cell-matrix Communication and Functions in Health and Disease" to encompass the broader scope of this meeting. The five scientific sessions covered various topics: Extracellular Matrix Proteins in Cell Communication and Signaling (Chaired by Brahim Chaqour and Vivi T. Monsen), Vascular Development and Pathophysiology (Chaired by Lester F. Lau and Håvard Attramadal), Mechanisms of Diseases (Chaired by George Bou-Gharios and Satoshi Kubota), Tissue Development and Homeostasis (Chaired by Blandine Poulet and Bernard Perbal), and Mechanisms of Disease: Cancer and the Matrix (Chaired by Stephen M. Twigg and Raymond B. Birge). The 2024 ICCNS Award was presented to Katia Scotlandi during the last session (Chaired by Bernard Perbal) before Håvard Attramadal presented the conclusion of the workshop.

The transcription coactivator YAP1 mediates the major effects of the Hippo signaling pathway. The CCN family is a small group of glycoproteins known to be downstream effectors of YAP1 in diverse tissues. However, whether CCN family members mediate the effects of YAP1 in human trophoblasts is unknown. In this study, placental expression of both YAP1 and CCN1 was found to be impaired in pregnancies complicated by early-onset severe preeclampsia. CCN1 was expressed not only in cytotrophoblasts, trophoblast columns, and mesenchymal cells, similar to active YAP1, but also in syncytiotrophoblasts of normal first-trimester placental villi; moreover, decidual staining of active YAP1 and CCN1 was found in both interstitial and endovascular extravillous trophoblasts. In cultured immortalized human trophoblastic HTR-8/SVneo cells, knockdown of YAP1 decreased CCN1 mRNA and protein expression and led to impaired cell invasion and migration. Also, CCN1 knockdown negatively affected HTR-8/SVneo cell invasion and migration but not viability. YAP1 knockdown was further found to impair HTR-8/SVneo cell viability via G0/G1 cell cycle arrest and apoptosis, while CCN1 knockdown had minimal effect on cell cycle arrest and no effect on apoptosis. Accordingly, treatment with recombinant CCN1 partially reversed the YAP1 knockdown-induced impairment in trophoblast invasion and migration but not in viability. Thus, CCN1 mediates the effects of YAP1 on human trophoblast invasion and migration but not apoptosis, and decreased placental expression of YAP1 and CCN1 in pregnancies complicated by early-onset severe preeclampsia might contribute to the pathogenesis of this disease.

The CCN family is a group of matricellular proteins associated with the extracellular matrix. This study aims to explore the role of the CCN family in glioma development and its implications in the tumor microenvironment. Through analysis of bulk RNA-seq cohorts, correlations between CCN family expression and glioma subtypes, patient survival, and bioactive pathway enrichment were investigated. Additionally, single-cell datasets were employed to identify novel cell subgroups, followed by analyses of cell communication and transcription factors. Spatial transcriptomic analysis was utilized to validate the CCN family's involvement in glioma. Results indicate overexpression of CYR61,CTGF, and WISP1 in glioma, associated with unfavorable subtypes and reduced survival. Enrichment analyses revealed associations with oncogenic pathways, while CTGF and WISP1 expression correlated with increased infiltration of regulatory T cells and M2 macrophages. Single-cell analysis identified MES-like cells as the highest CCN expression. Moreover, intercellular signal transduction analysis demonstrated active pathways, including SPP1-CD44, in cell subgroups with elevated CYR61 and CTGF expression. Spatial transcriptomic analysis confirmed co-localization of CYR61,CTGF and SPP1-CD44 with high oncogenic pathway activity. These findings suggest that CCN family members may serve as potential prognostic biomarkers and therapeutic targets for glioma.

Integrative multi-omics analysis reveals ortho-topolin riboside exhibits anticancer activity by regulating metabolic pathways in radio-resistant triple negative breast cancer cells

Recently, the pathomechanisms of keloids have been extensively researched using transcriptomic analysis, but most studies did not consider the activity of keloids. We aimed to profile the transcriptomics of keloids according to their clinical activity and location within the keloid lesion, compared with normal and mature scars. Tissue samples were collected (keloid based on its activity (active and inactive), mature scar from keloid patients and normal scar (NS) from non-keloid patients). To reduce possible bias, all keloids assessed in this study had no treatment history and their location was limited to the upper chest or back. Multiomics assessment was performed by using single-cell RNA sequencing and multiplex immunofluorescence. Increased mesenchymal fibroblasts (FBs) was the main feature in keloid patients. Noticeably, the proportion of pro-inflammatory FBs was significantly increased in active keloids compared to inactive ones. To explore the nature of proinflammatory FBs, trajectory analysis was conducted and CCN family associated with mechanical stretch exhibited higher expression in active keloids. For vascular endothelial cells (VECs), the proportion of tip and immature cells increased in keloids compared to NS, especially at the periphery of active keloids. Also, keloid VECs highly expressed genes with characteristics of mesenchymal activation compared to NS, especially those from the active keloid center. Multiomics analysis demonstrated the distinct expression profile of active keloids. Clinically, these findings may provide the future appropriate directions for development of treatment modalities of keloids. Prevention of keloids could be possible by the suppression of mesenchymal activation between FBs and VECs and modulation of proinflammatory FBs may be the key to the control of active keloids.