The aging of skin has important impact on various systems, and certain skin aging (SG) markers can not only help with early diagnosis, but also provide new ideas for pathophysiological research and treatment strategies.

To identify target genes related to SG through bioinformatics technology and provide ideas for skin anti-aging.

Differential expression genes (DEGs) related to SG were screened through transcriptome information from GEO datasets (GSE85358 and GSE670988). Based on eQTL and GWAS datasets, Mendelian Randomization (MR) analysis was applied to identify associations between gene expression and SG. Then, aging skin related important genes (AS-IGs) were obtained based on above two steps, and functional and pathway analyses were performed to explore the potential mechanisms AS-IGs in SG. Finally, the CIBERSORT evaluation was used to assess the infiltration of immune cells related to SG.

Seven AS-IGs were selected through intersection from 612 DEGs and 399 eQTL genes. Then, enrichment analysis results showed there were 60 GO terms may involved in the process of SG, like fatty-acyl-CoA metabolic process, while KEGG enrichment pathways identified mainly involved in mechanisms related to fatty acid metabolism, energy generation, and inflammation regulation. The CIBERSORT evaluation showed that NK cells resting were the main infiltrating cells.

AS-IGs may play important roles in the process of SG in the body. These molecules involve multiple systems and mechanisms in the body, such as immune function, metabolic function, and neuroendocrine function.

The tumor microenvironment plays a crucial role in the progression of both glioma and glioma-induced autoimmune encephalitis. However, there remains a significant lack of effective therapeutic targets for these diseases.

We collected 54 CT images of glioma patients and 54 glioma-induced autoimmune encephalitis patients, respectively. Radiomics features were extracted from tumors and encephalitis regions using Python, followed by dimensionality reduction via random forest and lasso regression, and construction of radiomics-based risk scores. Genomic data matched with clinical information were analyzed to identify key prognostic genes significantly associated with risk scores. Gene expression was validated by immunohistochemistry using our clinical samples. Immune infiltration was evaluated using five algorithms (MCP-counter, EPIC, TIMER, QUANT and IPS). The association between hub genes and immune checkpoint markers as well as immunoregulation-related genes was also analyzed using Spearman correlation.

We identified 980 radiomics features both in glioma and encephalitis patient images and selected four key features through lasso regression to build a radiomics-based risk score. COL22A1 was strongly correlated with the risk score and identified as the hub prognostic gene. COL22A1 expression was higher in glioblastoma tissues and cell lines, and correlated with clinical factors such as higher age, WHO grade, and IDH mutation status. Immune infiltration analysis indicated associations with diverse immune and stromal cell populations, including CD8+T cells, macrophages, and CAFs. COL22A1 was also positively correlated with immune checkpoints and immune-regulated genes.

Our study highlights the critical role of COL22A1 in gliomas and glioma-Induced Autoimmune Encephalitis, demonstrating its strong association with poor prognosis and its significant involvement in tumor immune regulation.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). Given their various roles in tumor progression and treatment resistance, CAFs are promising therapeutic targets in cancer. The elimination of tumor-promoting CAFs has been investigated in various animal models to determine whether it effectively suppresses tumor growth. Based on recent evidence, several simple strategies have been proposed to eliminate tumor-promoting CAFs and attenuate these features. In addition, attention has focused on the critical role that CAFs play in the immunosuppressive TME. Therefore, the functional reprogramming of CAFs in combination with immune checkpoint inhibitors has also been investigated as a possible therapeutic approach. However, although potential targets in CAFs have been widely characterized, the plasticity and heterogeneity of CAFs complicate the understanding of their properties and present difficulties for clinical application. Moreover, the identification of tumor-suppressive CAFs highlights the necessity for the development of therapeutic approaches that can distinguish and switch between tumor-promoting and tumor-suppressive CAFs in an appropriate manner. In this review, we introduce the origins and diversity of CAFs, their role in cancer, and current therapeutic strategies aimed at targeting CAFs, including ongoing clinical evaluations.

In addition to their traditional roles in maintaining tissue morphology and organ development, emerging evidence suggests that collagen (COL) remodeling-referring to dynamic changes in the quantity, stiffness, arrangements, cleavage states, and homo-/hetero-trimerization of COLs-serves as a key signaling mechanism that governs tumor growth and metastasis. COL receptors act as switches, linking various forms of COL remodeling to different cell types during cancer progression, including cancer cells, immune cells, and cancer-associated fibroblasts. In this review, we summarize recent findings on the signaling pathways mediated by COL arrangement, cleavage, and trimerization states (both homo- and hetero-), as well as the roles of the primary COL receptors-integrin, DDR1/2, LAIR-1/2, MRC2, and GPVI-in cancer progression. We also discuss the latest therapeutic strategies targeting COL fragments, cancer-associated fibroblasts, and COL receptors, including integrins, DDR1/2, and LAIR1/2. Understanding the pathways modulated by COL remodeling and COL receptors in various pathological contexts will pave the way for developing new precision therapies.

Antigen-presenting fibroblasts are a newly recognized subset that challenges the traditional view of these cells as mere structural components. Under pathological or environmental stimuli, fibroblasts acquire antigen-presenting capabilities through the expression of MHC-II molecules and co-stimulatory factors, enabling them to interact with T cells and modulate immune responses. These specialized fibroblasts have been identified across various tissues and diseases, where they play context-dependent roles, either amplifying immune dysregulation or contributing to immune homeostasis. This review synthesizes recent advances in understanding the origins, activation, and functions of antigen-presenting fibroblasts. It highlights their role in promoting pathogenic immune responses and offering therapeutic opportunities through targeted modulation. Advancing our understanding of antigen-presenting fibroblasts holds great promise for developing innovative approaches to immune modulation and therapy across a range of diseases.

The extracellular matrix (ECM) controls tumour dissemination. We characterise ECM organization in human and mouse tumours, identifying three regions: tumour body, proximal invasive front and distal invasive front. Invasive areas show increased matrix density, fibre thickness, length, and alignment, with unique radial fibre orientation at the distal invasive front correlating with amoeboid invasive features. Using patient samples and murine models, we find that metastases recapitulate ECM features of the primary tumour. Ex vivo culture of murine cancer cells isolated from the different tumour regions reveals a spatial cytoskeletal and transcriptional memory. Several in vitro models recapitulate the in vivo ECM organisation showing that increased matrix induces 3D confinement supporting Rho-ROCK-Myosin II activity, while radial orientation enhances directional invasion. Spatial transcriptomics identifies a mechano-inflammatory program associated with worse prognosis across multiple tumour types. These findings provide mechanistic insights into how ECM organization shapes local invasion and distant metastasis.

In breast cancer (BC), radial alignment of collagen fibers at the tumor-matrix interface facilitates collective invasion of cancer cells into the surrounding stromal matrix, a critical step toward metastasis. Collagen remodeling is driven by proteases and cellular forces, mediated by matrix mechanical plasticity, or irreversible matrix deformation in response to force. However, the specific mechanisms causing collagen radial alignment remain unclear. Here, we study collective invasion of BC tumor spheroids in collagen-rich matrices. Increasing plasticity to BC-relevant ranges facilitates invasion, with increasing stiffness potentiating a transition from single cell to collective invasion. At enhanced plasticity, cells radially align collagen at the tumor-matrix interface prior to invasion. Surprisingly, cells migrate tangentially to the tumor-matrix interface in a swirling-like motion, perpendicular to the direction of alignment. Mechanistically, swirling generates local shear stresses, leading to distally propagating contractile radial stresses due to negative normal stress, an underappreciated property of collagen-rich matrices. These contractile stresses align collagen fibers radially, facilitating collective invasion. The basement membrane (BM), which separates epithelia from stroma in healthy tissues, acts as a mechanical insulator by preventing swirling cells from aligning collagen. Thus, after breaching the BM, swirling of BC cells at the tumor-stroma interface radially aligns collagen to facilitate invasion.

Metastatic melanoma is an aggressive and deadly form of skin cancer, known for its rapid ability to spread to other organs. Melanoma metastasis involves several steps: Local invasion, lymphovascular invasion and proliferation to new sites. This process is facilitated by genetic alterations, interactions with the tumor microenvironment and evasion of the immune system. Despite advances in therapies, the 5-year survival rate remains low at ~22.5%. Notably, current research is focused on identifying patients who may benefit from specific treatments, considering factors such as mutational load and programmed death ligand 1 expression. BRAF inhibitors and immune checkpoint inhibitors have improved survival, although numerous patients do not respond or develop resistance, underscoring the need for novel biomarkers to optimize treatment and monitoring of the disease. In summary, the purpose of the present article is to review the different serological, histological, microRNA and circulating tumor cell biomarkers that have proven useful in the diagnosis, follow-up and prognosis of metastatic melanoma. These biomarkers represent a promising area for research and clinical application, with the aim of offering more precise and personalized treatments.

Immunity suffers a function deficit during aging, and the incidence of cancer is increased in the elderly. However, most cancer models employ young mice, which are poorly representative of adult cancer patients. We have previously reported that Triple-Therapy (TT), involving antigen-presenting-cell activation by vinorelbine and generation of TCF1+-stem-cell-like T cells (scTs) by cyclophosphamide significantly improved anti-PD-1 efficacy in anti-PD1-resistant models like Triple-Negative Breast Cancer (TNBC) and Non-Hodgkin's Lymphoma (NHL), due to T-cell-mediated tumor killing. Here, we describe the effect of TT on TNBC growth and on tumor-microenvironment (TME) of young (6-8w, representative of human puberty) versus adult (12 m, representative of 40y-humans) mice. TT-efficacy was similar in young and adults, as CD8+ scTs were only marginally reduced in adults. However, single-cell analyses revealed major differences in the TME: adults had fewer CD4+ scTs, B-naïve and NK-cells, and more memory-B-cells. Cancer-associated-fibroblasts (CAF) with an Extracellular Matrix (ECM) deposition-signature (Matrix-CAFs) were more common in young mice, while pro-inflammatory stromal populations and myofibroblasts were more represented in adults. Matrix-CAFs in adult mice displayed decreased ECM-remodeling abilities, reduced collagen deposition, and a different pattern of interactions with the other cells of the TME. Taken together, our results suggest that age-dependent differences in the TME should be considered when designing preclinical studies.

We present an easy-to-use, disposable, thermoplastic microwell chip designed to support screening and high-resolution imaging of single-cell behavior in two- and three-dimensional (2D and 3D) cell cultures. We show that the chip has excellent optical properties and provide simple protocols for efficient long-term cell culture of suspension and adherent cells, the latter grown either as monolayers or as hundreds of single, uniformly sized spheroids. We then demonstrate the applicability of the system for single-cell analysis by correlating the dynamic cytotoxic response of single immune cells grown under different metabolic conditions to their intracellular cytolytic load at the end of the assay. Additionally, we illustrate highly multiplex cytotoxicity screening of tumor spheroids in the chip, comparing the effect of environment cues characteristic of the tumor microenvironment on natural killer (NK)-cell-induced killing. Following the functional screening, we perform high-resolution 3D immunofluorescent imaging of infiltrating NK cells within the spheroid volumes.

Thrombomodulin (TM), a transmembrane glycoprotein, has emerged as a key factor in the metastatic spread of various cancers, including malignant melanoma. Despite its recognized significance, the underlying mechanisms of TM's involvement in enhancing metastasis remain incompletely understood. This study addresses this knowledge gap by utilizing spatial and interfacial invasion models in vitro to investigate the effect of the interaction between TM and plasminogen (Plg) on melanoma invasion. While it is well established that Plg induces a chain reaction in the plasmin system, leading to the activation of metalloproteases that promote tumor cell invasion and metastasis, this study is the first to demonstrate that TM binding to Plg can enhance these activations in spatial and interfacial invasion models in vitro. These results highlight the potential of TM as a crucial target for the development of drugs aimed at significantly inhibiting melanoma metastasis and improving patient survival.

To date, genetically modified organoids are emerging as a promising 3D modeling tool aimed at solving genetically relevant clinical and biomedical problems for regenerative medicine and tissue engineering. As an optimal vehicle for gene delivery, genetically modified organoids can enhance or reduce the expression of target genes through virus and non-virus-based gene transfection methods to achieve tissue regeneration. Animal experiments and preclinical studies have demonstrated the beneficial role of genetically modified organoids in various aspects of organ regeneration, including thymus, lacrimal glands, brain, lung, kidney, photoreceptors, etc. Furthermore, the technology offers a potential treatment option for various diseases, such as Fabry disease, non-alcoholic steatohepatitis, and Lynch syndrome. Nevertheless, the uncertain safety of genetic modification, the risk of organoid application, and bionics of current genetically modified organoids are still challenging. This review summarizes the researches on genetically modified organoids in recent years, and describes the transfection methods and functions of genetically modified organoids, then introduced their applications at length. Also, the limitations and future development directions of genetically modified organoids are included.

The physical characteristics of the tumor microenvironment (TME) include solid stress, interstitial fluid pressure, tissue stiffness and microarchitecture. Among them, abnormal changes in tissue stiffness hinder drug delivery, inhibit infiltration of immune killer cells to the tumor site, and contribute to tumor resistance to immunotherapy. Therefore, targeting tissue stiffness to increase the infiltration of drugs and immune cells can offer a powerful support and opportunities to improve the immunotherapy efficacy in solid tumors. In this review, we discuss the mechanical properties of tumors, the impact of a stiff TME on tumor cells and immune cells, and the strategies to modulate tumor mechanics.

The skin seems to rejuvenate upon exposure to factors within the circulation of young organisms. Intrinsic factors that modulate skin aging are poorly understood. We used heterochronic parabiosis and aptamer-based proteomics to identify serum-derived rejuvenating factors. We discovered a novel extracellular function of hyaluronan and proteoglycan link protein 1 (HAPLN1). Its serum levels decreased with age, disturbing the integrity of the skin extracellular matrix, which is predominantly composed of collagen I and hyaluronan; levels of various markers, which decrease in aged skin, were significantly restored in vivo and in vitro by the administration of recombinant human HAPLN1 (rhHAPLN1). rhHAPLN1 protected transforming growth factor beta receptor 2 on the cell surface from endocytic degradation via mechanisms such as regulation of viscoelasticity, CD44 clustering. Moreover, rhHAPLN1 regulated the levels of nuclear factor erythroid 2-related factor 2, phosphorylated nuclear factor kappa B, and some cyclin-dependent kinase inhibitors such as p16 and p21. Therefore, rhHAPLN1 may act as a novel biomechanical signaling protein to rejuvenate aged skin.

Despite considerable advancements in cancer immunotherapy, advanced melanoma still presents a substantial clinical challenge. In an effort to explore treatment options, we examined the immunotherapeutic potential of effector Vγ9Vδ2-T cells in vitro in a three-dimensional (3D) human organotypic melanoma-in-skin (Mel-RhS) model.

Vγ9Vδ2-T cells were introduced into Mel-RhS via intradermal injection and cultured within the tissue microenvironment for up to 3 days.

Vγ9Vδ2-T cells remained viable for up to 3 days and were in close proximity to or within tumor nests. Upon Mel-RhS dissociation, a fraction was shown to be decorated by melanoma-associated chondroitin sulfate proteoglycan (MCSP), demonstrating their ability to actively navigate the tumor microenvironment and trogocytose cancer cells. Investigation into the apparent trogocytosis revealed an enhanced activated state of MCSP-decorated Vγ9Vδ2-T cells, evidenced by increased expression levels of 4-1BB, NKp44, programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1), compared with their MCSP- counterpart. These findings suggest that Vγ9Vδ2-T cells, upon successfully contacting melanoma cells, actively recognize and acquire MCSP from these malignant cells. Evidence of actual tumor cell elimination, although not significant, was only obtained after preincubation of Mel-RhS with pamidronate, a phosphoantigen-inducing agent, indicating the need for additional T cell receptor-mediated signaling for Vγ9Vδ2-T cells to reach their full oncolytic potential.

This study highlights the viability and persistence of Vγ9Vδ2-T cells within the 3D microenvironment, their migratory and antitumor functionality, and the suitability of the model for testing T cell-based therapies, contributing both to the understanding of Vγ9Vδ2-T cell biology and their application in cancer immunotherapy.

The pharmaceutical and cosmetic industries are encountering a challenge in adopting new study models for product development. there has been a growing interest in organ-on-a-chip systems, and particularly for generating skin models. While numerous alternatives replicating high-fidelity skin models exist, there is a notable absence of melanoma study's methodology specifically on these microfluidic chips. This work introduces a novel skin-on-a-chip device featuring two microfluidic chambers, facilitating a 3D cell co-culture involving fibroblasts, keratinocytes, and melanoma cells. The design of this organ-on-a-chip has enabled the administration of the anticancer treatment Gemcitabine using an injection system within the chip. The results of this work have shown a significant impact on the co-culture distribution of cells, decreasing the population of cancerous cells after the administration of Gemcitabine. The work presented in this article demonstrates the effectiveness of the chip and the administration method for testing anti-melanoma therapies and position this technology as an enhanced fidelity model for studying melanoma while providing an alternative for real-time monitoring of drug testing.

3D skin models have been explored as an alternative method to the use of animals in research and development. Usually, human skin equivalents comprise only epidermis or epidermis/dermis layers. Herein, we leverage 3D bioprinting technology to fabricate a full-thickness human skin equivalent with hypodermis (HSEH). The collagen hydrogel-based structure provides a mimetic environment for skin cells to adhere, proliferate and differentiate. The effective incorporation of the hypodermis layer is evidenced by scanning electron microscopy, immunofluorescence, and hematoxylin and eosin staining. The transcriptome results underscore the pivotal role of the hypodermis in orchestrating the genetic expression of a multitude of genes vital for skin functionality, including hydration, development and differentiation. Accordingly, we evidence the paramount significance of full-thickness human skin equivalents with hypodermis layer to provide an accurate in vitro platform for disease modeling and toxicology studies.

Modern cancer management comprises a variety of treatment strategies. Immunotherapy, while successful at treating many cancer subtypes, is often hindered by tumor immune evasion and T cell exhaustion as a result of an immunosuppressive tumor microenvironment (TME). In solid malignancies, the extracellular matrix (ECM) embedded within the TME plays a central role in T cell recognition and cancer growth by providing structural support and regulating cell behavior. Relative to healthy tissues, tumor associated ECM signatures include increased fiber density and alignment. These and other differentiating features contributed to variation in clinically observed tumor-specific ECM configurations, collectively referred to as Tumor-Associated Collagen Signatures (TACS) 1-3. TACS is associated with disease progression and immune evasion. This review explores our current understanding of how ECM geometry influences the behaviors of both immune cells and tumor cells, which in turn impacts treatment efficacy and cancer evolutionary progression. We discuss the effects of ECM remodeling on cancer cells and T cell behavior and review recent in silico models of cancer-immune interactions.

The extracellular matrix (ECM) is the complex meshwork of proteins and glycans that forms the scaffold that surrounds and supports cells. It exerts key roles in all aspects of metazoan physiology, from conferring physical and mechanical properties on tissues and organs to modulating cellular processes such as proliferation, differentiation and migration. Understanding the mechanisms that orchestrate the assembly of the ECM scaffold is thus crucial to understand ECM functions in health and disease. This Review discusses novel insights into the compositional diversity of matrisome components and the mechanisms that lead to tissue-specific assemblies and architectures tailored to support specific functions. The Review then highlights recently discovered mechanisms, including post-translational modifications and metabolic pathways such as amino acid availability and the circadian clock, that modulate ECM secretion, assembly and remodelling in homeostasis and human diseases. Last, the Review explores the potential of 'matritherapies', that is, strategies to normalize ECM composition and architecture to achieve a therapeutic benefit.

Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.

Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis.

We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.

Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

UVB radiation induces oxidative stress, DNA damage, and inflammation, leading to skin wrinkling, compromised barrier function, and an increased risk of carcinogenesis. Addressing or preventing photoaging may offer a promising therapeutic avenue for these conditions. Recent research indicated that mesenchymal stem cells (MSCs) exhibit significant therapeutic potential for various skin diseases. Given that extracellular vesicles (EV) can deliver diverse cargo to recipient cells and elicit similar therapeutic effects, we investigated the roles and underlying mechanisms of both adipose-derived MSC-derived EV (AMSC-EV) and umbilical cord-derived MSC-derived EV (HUMSC-EV) in photoaging. Our findings indicated that in vivo, treatment with AMSC-EV and HUMSC-EV resulted in improvements in wrinkles and skin hydration while also mitigating skin inflammation and thickness alterations in both the epidermis and dermis. Additionally, in vitro studies using human keratinocytes (HaCaTs), human dermal fibroblast cells (HDFs), and T-Skin models revealed that AMSC-EV and HUMSC-EV attenuated senescence, reduced levels of reactive oxygen species (ROS) and DNA damage, and alleviated inflammation induced by UVB. Furthermore, EV treatment enhanced cell viability and migration capacity in the epidermis and promoted extracellular matrix (ECM) remodeling in the dermis in photoaged cell models. Mechanistically, proteomics results showed that TIMP1 was highly expressed in both AMSC-EV and HUMSC-EV and could exert similar effects as MSC-EV. In addition, we found that EV and TIMP1 could inhibit Notch1 and downstream targets Hes1, P16, P21, and P53. Collectively, our data suggests that both AMSC-EV and HUMSC-EV attenuate skin photoaging through TIMP1/Notch1.

The integumentary system serves as a crucial protective barrier and is subject to complex signaling pathways that regulate its physiological functions. As the body's first line of defense, the skin is continuously exposed to environmental stressors, necessitating a robust network of signaling molecules to maintain homeostasis. Considering the main cellular components to be keratinocytes, melanocytes, fibroblasts, and fibrous components, collagen of various types, this review explores the intricate signaling mechanisms that govern skin integrity, focusing on key pathways involved in impacts of ageing and environment factors on skin health. The role of growth factors, cytokines, hormones and other molecular mediators in these processes is examined. Specially for women, decrease of estrogen is determinant to alter signaling and to compromise skin structure, especially the dermis. Environmental factors, such as ultraviolet rays and pollution alongside the impact of ageing on signaling pathways, especially TGF-β and proteases (metalloproteinases and cathepsins). Furthermore, with advancing age, the skin's capacity to shelter microbiome challenges diminishes, leading to alterations in signal transduction and subsequent functional decline. Understanding these age-related changes is essential for developing targeted therapies aimed at enhancing skin health and resilience, but also offers a promising avenue for the treatment of skin disorders and the promotion of healthy ageing.

Limited activation and infiltration of CD8+ T cells are major challenges facing T cell-based immunotherapy for most solid tumors, of which the mechanism is multilayered and not yet fully understood.

Levels of CD93 expression on monocytes from paired non-tumor, peritumor and tumor tissues of human hepatocellular carcinoma (HCC) were evaluated. The underlying mechanisms mediating effects of CD93+ monocytes on the inhibition and tumor exclusion of CD8+ T cells were studied through both in vitro and in vivo experiments.

In this study, we found that monocytes in the peritumoral tissues of HCC significantly increased levels of CD93 expression, and these CD93+ monocytes collocated with CD8+ T cells, whose density was much higher in peritumor than intratumor areas. In vitro experiments showed that glycolytic switch mediated tumor-induced CD93 upregulation in monocytes via the Erk signaling pathway. CD93 on the one hand could enhance PD-L1 expression through the AKT-GSK3β axis, while on the other hand inducing monocytes to produce versican, a type of matrix component which interacted with hyaluronan and collagens to inhibit CD8+ T cell migration. Consistently, levels of CD93+ monocytes positively correlated with the density of peritumoral CD8+ T cells while negatively correlated with that of intratumoral CD8+ T cells. Targeting CD93 on monocytes not only increased the infiltration and activation of CD8+ T cells but also enhanced tumor sensitivity to anti-PD-1 treatment in mice in vivo.

This study identified an important mechanism contributing to the activation and limited infiltration of CD8+ T cells in solid tumors, and CD93+ monocytes might represent a plausible immunotherapeutic target for the treatment of HCC.

There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRAF/MEK inhibition.

Skin aging is the most obvious feature of human aging, and delaying aging has become a hot and difficult research topic in aesthetic medicine. The accumulation of dysfunctional senescent cells is one of the important mechanisms of skin aging, based on which a series of anti-aging strategies have been generated. In this paper, from the perspective of cellular senescence, we utilize bibliometrics and research review to explore the research hotspots and trends in this field, with a view to providing references for skin health and aesthetic medicine.

We obtained literature related to this field from the Web of Science Core Collection database from 1994 to 2024. Bibliometrix packages in R, CiteSpace, VOSviewer, Origin, and Scimago Graphica were utilized for data mining and visualization.

A total of 2,796 documents were included in the analysis. The overall trend of publications showed a continuous and rapid increase from 2016-2023, but the total citations improved poorly over time. In this field, Journal of Cosmetic Dermatology, Journal of Investigative Dermatology, Experimental Gerontology are core journals. Kim J, Lee JH, Lee S, Rattan SIS, Chung JH and Kim JH are the core authors in this field. Seoul National University is the first in terms of publications. Korea is the country with the most publications, but USA has the most total citations. Top 10 keywords include: gene-expression, skin, cellular senescence, cell, oxidative stress, antioxidants, in vitro, fibroblasts, mechanism, cancer. Current research trends are focused on neurodegeneration, skin rejuvenation, molecular docking, fibrosis, wound healing, SASP, skin barrier, and antioxidants. The core literature and references reflect topics such as the major molecular pathways in the aging process, and the relationship with tumors.

This field of research has been rapidly rising in recent years. Relevant research hotspots focus on oxidative stress, fibroblasts, and senescence-associated secretory phenotype. Anti-aging strategies targeting cellular senescence hold great promise, including removal of senescent cells or attenuation of SASP factors, corresponding to senolytics and senomorphics therapies, respectively.

Solid tumours comprise cancer cells that engage in continuous interactions with non-malignant cells and with acellular components, forming the tumour microenvironment (TME). The TME has crucial and diverse roles in tumour progression and metastasis, and substantial efforts have been dedicated into understanding the functions of different cell types within the TME. These efforts highlighted the importance of non-cell-autonomous signalling in cancer, mediating interactions between the cancer cells, the immune microenvironment and the non-immune stroma. Much of this non-cell-autonomous signalling is mediated through acellular components of the TME, known as the extracellular matrix (ECM), and controlled by the cells that secrete and remodel the ECM - the cancer-associated fibroblasts (CAFs). In this Review, we delve into the complex crosstalk among cancer cells, CAFs and immune cells, highlighting the effects of CAF-induced ECM remodelling on T cell functions and offering insights into the potential of targeting ECM components to improve cancer therapies.

Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.

Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

Despite extensive research and improvements in understanding colorectal cancer (CRC), its metastatic form continues to pose a substantial challenge, primarily owing to limited therapeutic options and a poor prognosis. This Review addresses the emerging focus on metastatic CRC (mCRC), which has historically been under-studied compared with primary CRC despite its lethality. We delve into two crucial aspects: the molecular and cellular determinants facilitating CRC metastasis and the principles guiding the evolution of metastatic disease. Initially, we examine the genetic alterations integral to CRC metastasis, connecting them to clinically marked characteristics of advanced CRC. Subsequently, we scrutinize the role of cellular heterogeneity and plasticity in metastatic spread and therapy resistance. Finally, we explore how the tumour microenvironment influences metastatic disease, emphasizing the effect of stromal gene programmes and the immune context. The ongoing research in these fields holds immense importance, as its future implications are projected to revolutionize the treatment of patients with mCRC, hopefully offering a promising outlook for their survival.

Bladder cancer (BC) is very common among cancers of urinary system. It was usually categorized into two types: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). NMIBC and MIBC groupings are heterogeneous and have different characteristics.

The study was aimed to find some hub genes and related signal pathways which might be engaged in the progression of BC and to investigate the relationship with clinical stages and its prognostic significance.

GSE37317 datasets were acquired from Gene Expression Omnibus (GEO) database. GEO2R on-line tool was selected to screen the differentially expressed genes (DEGs) of the two different types of BC. Then, Gene Ontology (GO) enrichment and KOBAS-Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these DEGs were conducted. A protein-protein interaction (PPI) network was employed to help us screen hub genes and find significant modules. Finally, we made analysis of gene expression and survival curve by GEPIA and Kaplan-Meier plotter database.

224 DEGs were screened in total, with 110 showing increased expression and 114 demonstrating decreased expression. GO and KEGG pathway enrichment analysis showed that DEGs were mostly involved in collagen fibril organization, extracellular matrix (ECM) structural constituent, bHLH transcription factor binding, AGE-RAGE signaling pathway and TGF-beta signaling pathway. Only 3 hub genes (DCN, JUN, THBS1) displayed significantly higher expression compared to those in the healthy controls. These hub genes were also strongly related to clinical stages as well as overall survival (OS) of BC patients.

Taken together, most of hub genes involved in the progression of BC were related to ECM and EMT. In addition, 3 hub genes (DCN, JUN, THBS1) were strongly related with clinical stages and OS of BC patients. This study can enhance our comprehension of the progression of NMIBC and identify novel potential targets for MIBC.

Aged patients with melanoma (>65 years old) have more aggressive disease relative to young patients (<55 years old) for reasons that are not completely understood. Analysis of the young and aged secretome from human dermal fibroblasts identified >5-fold levels of IGF-binding protein 2 (IGFBP2) in the aged fibroblast secretome. IGFBP2 functionally triggers upregulation of the PI3K-dependent fatty acid biosynthesis program in melanoma cells. Melanoma cells co-cultured with aged dermal fibroblasts have higher levels of lipids relative to those co-cultured with young dermal fibroblasts, which can be lowered by silencing IGFBP2 expression in fibroblasts prior to treating with conditioned media. Conversely, ectopically treating melanoma cells with recombinant IGFBP2 in the presence of conditioned media from young fibroblasts or overexpressing IGFBP2 in melanoma cells promoted lipid synthesis and accumulation in melanoma cells. Treatment of young mice with rIGFBP2 increases tumor growth. Neutralizing IGFBP2 in vitro reduces migration and invasion in melanoma cells, and in vivo studies demonstrate that neutralizing IGFBP2 in syngeneic aged mice reduces tumor growth and metastasis. Our results suggest that aged dermal fibroblasts increase melanoma cell aggressiveness through increased secretion of IGFBP2, stressing the importance of considering age when designing studies and treatment.

The aged microenvironment drives metastasis in melanoma cells. This study reports that IGFBP2 secretion by aged fibroblasts induces lipid accumulation in melanoma cells, driving an increase in tumor invasiveness. Neutralizing IGFBP2 decreases melanoma tumor growth and metastasis.

Gastric cancer is a highly heterogeneous disease, presenting a major obstacle to personalized treatment. Effective markers of the immune checkpoint blockade response are needed for precise patient classification. We, therefore, divided patients with gastric cancer according to collagen gene expression to indicate their prognosis and treatment response.

We collected data for 1250 patients with gastric cancer from four cohorts. For the TCGA-STAD cohort, we used consensus clustering to stratify patients based on expression levels of 44 collagen genes and compared the prognosis and clinical characteristics between collagen subtypes. We then identified distinct transcriptomic and genetic alteration signatures for the subtypes. We analyzed the associations of collagen subtypes with the responses to chemotherapy, immunotherapy, and targeted therapy. We also established a platform-independent collagen-subtype predictor. We verified the findings in three validation cohorts (GSE84433, GSE62254, and GSE15459) and compared the collagen subtyping method with other molecular subtyping methods.

We identified two subtypes of gastric adenocarcinoma: a high-expression collagen subtype (CS-H) and a low-expression collagen subtype (CS-L). Collagen subtype was an independent prognostic factor, with better overall survival in the CS-L subgroup. The inflammatory response, angiogenesis, and phosphoinositide 3-kinase (PI3K)/Akt pathways were transcriptionally active in the CS-H subtype, while DNA repair activity was significantly greater in the CS-L subtype. PIK3CA was frequently amplified in the CS-H subtype, while PIK3C2A, PIK3C2G, and PIK3R1 were frequently deleted in the CS-L subtype. CS-H subtype tumors were more sensitive to fluorouracil, while CS-L subtype tumors were more sensitive to immune checkpoint blockade. CS-L subtype was predicted to be more sensitive to HER2-targeted drugs, and CS-H subtype was predicted to be more sensitive to vascular endothelial growth factor and PI3K pathway-targeting drugs. Collagen subtyping also has the potential to be combined with existing molecular subtyping methods for better patient classification.

We classified gastric cancers into two subtypes based on collagen gene expression and validated these subtypes in three validation cohorts. The collagen subgroups differed in terms of prognosis, clinical characteristics, transcriptome, and genetic alterations. The subtypes were closely related to patient responses to chemotherapy, immunotherapy, and targeted therapy.

Excessive inflammatory response and oxidative stress (OS) play an important role in the pathogenesis of spinal cord injury (SCI). Balance of inflammation and prevention of OS have been considered an effective strategy for the treatment of SCI. Hyaluronan and proteoglycan link protein 1 (HAPLN1), also known as cartilage link protein, has displayed a wide range of biological and physiological functions in different types of tissues and cells. However, whether HAPLN1 regulates inflammation and OS during SCI is unknown. Therefore, we aimed to examine whether HAPLN1 can have a protective effect on SCI. In this study, both in vitro and in vivo SCI models were established. Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining assays were used. Western blotting and enzyme-linked immunosorbent assay were employed to assess the expression of proteins. Our results demonstrate that the administration of HAPLN1 promoted the recovery of motor neurons after SCI by increasing the Basso mouse scale score, increasing the numbers of motor neurons, and preventing apoptosis of spinal cord cells. Additionally, HAPLN1 mitigated OS in spinal cord tissue after SCI by increasing the content of superoxide dismutase SOD and the activity of glutathione peroxidase but reducing the levels of malondialdehyde. Importantly, we found that HAPLN1 stimulated the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and stimulated the expression of heme oxygenase-1 and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase-1, which mediated the attenuation of HAPLN1 in activation of the NOD-like receptor protein 3 (NLRP3) inflammasome by reducing the levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β. Correspondingly, in vitro experiments show that the presence of HAPLN1 suppressed the NLRP3 inflammasome and prevented cell injury against H2O2 in PC12 cells. These effects were mediated by the Nrf2/ARE pathway, and inhibition of Nrf2 with ML385 abolished the beneficial effects of HAPLN1. Based on these findings, we conclude that HAPLN1 inhibits the NLRP3 inflammasome through the stimulation of the Nrf2/ARE pathway, thereby suppressing neuroinflammation, enhancing motor neuronal survival, and improving the recovery of nerve function after SCI.

The tumor microenvironment (TME) in non-muscle-invasive bladder cancer (NMIBC) plays an important role in the anticancer response. We aimed to identify the prognostic biomarkers in the TME of patients with NMIBC for progression to ≥T2.

From our institutional database, 40 patients with T1 high-risk NMIBC who progressed were pair matched for Club Urologico Español de Tratamiento Oncologico (CUETO) progression variables with 80 patients who never progressed despite longer follow-up. Progression was defined as ≥T2 or extravesical disease. Patients were treated at least with bacillus Calmette-Guérin (BCG) induction (five or more of six doses). Immunohistochemical (IHC) markers for the TME were used on tissue at first T1 diagnosis: CD8-PanCK, GZMB-CD8-FOXP3, CD163, PD-L1 SP142/SP263, fibroblast activation protein-α (FAP), and CK5-GATA3. Full tissue slides were annotated digitally. Relative marker area (IHC-positive area/total area) or density (IHC-positive cells per area; n/mm2) was calculated, differentiating between regions of interest (ROIs; T1, Ta, and carcinoma in situ) and between compartments (stromal, epithelial, and combined). Differences in IHC variables were assessed using the t test, for continuous variables using analysis of variance and comparisons of more than two groups using Tukey's test. Conditional logistic regression for progression at 5-yr follow-up was performed with clusters based on pair matching.

Only FAP expression (increase per 50%) in T1 (odds ratio [OR]: 1.33; 95% confidence interval [CI]: 1.04-1.70) and all ROIs combined (OR: 1.62; 95% CI: 1.14-2.29) correlated significantly with progression. None of the other clinicopathological/IHC variables correlated with progression.

FAP is a potential prognostic biomarker for progression in high-risk NMIBC. FAP is a marker for cancer-associated fibroblasts and is linked to immunosuppression and neoangiogenesis, which makes future investigation clinically relevant.

We found that progression of high-risk non-muscle-invasive bladder cancer to muscle-invasive disease is less in patients with lower fibroblast activation protein-α (FAP) expression, which is a marker for cancer-associated fibroblasts.