Tumor Prognosis Research Articles

Progress of research on glucose transporter proteins in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs’ roles in HCC and to determine the most effective ways to translate these findings into clinical practice.

Mesenchymal stem cells and fibroblasts contribute to microvascular proliferation in glioblastoma and are correlated with immunosuppression and poor outcome.

Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma (GBM) and other World Health Organization (WHO) grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single cell RNA-sequencing (scRNA-seq) on paired CD45-CD105+ vascular/perivascular stromal cells (PVSCs) and CD45+CD105± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally-related mesenchymal stem cells (MSCs) alongside cancer-associated fibroblasts (CAFs), pericytes, fibromyocytes, and smooth muscle cells within the CD45-CD105+ compartment. RNA velocity analysis identified PDGFRB as a putative driver gene guiding MSCs toward more mature PVSCs in the context of MVP. Signaling network analysis and digital spatial profiling uncovered interactions between PDGFRB+ PVSCs and immunosuppressive myeloid cell subsets enriched in the perivascular niche, suggesting targetable receptor-ligand interactions. Additionally, a gene signature of MVP-associated PVSCs from gliomas predicted worse prognosis in multiple other solid tumors. This study provides a transcriptomic cell atlas of PVSCs and immune cells in glioma, helping to refine the biological model of MVP which has traditionally focused on endothelial cells.

Single-cell sequencing reveals the role of aggrephagy-related patterns in tumor microenvironment, prognosis and immunotherapy in endometrial cancer

BackgroundAs a type of autophagy, aggrephagy degrades the aggregation of misfolded protein in cells and plays an important role in key genetic events for various cancers. However, aggrephagy functions within the tumor microenvironment (TME) in endometrial cancer (EC) remain to be elucidated.MethodsA total of 36,227 single cells from single-cell RNA-seq data derived from five EC tumor samples were comprehensively analyzed using a nonnegative matrix factorization (NMF) algorithm for 44 aggrephagy-related genes. Bulk RNA-seq cohorts from public repositories were utilized to assess the prognostic value of aggrephagy-related TME clusters and predict immune checkpoint blockade immunotherapeutic response in EC.ResultsFibroblasts, macrophages, CD8+T cells, and lymphatic endothelial cells were categorized into two to five aggrephagy-related subclusters, respectively. CellChat analysis showed that the aggrephagy-related subtypes of TME cells exhibited extensive interactions with tumor epithelial cells, particularly for macrophages. Moreover, aggrephagy regulators may be significantly associated with the pseudotime trajectories of major TME cell types as well as the clinical and biological features of EC. Bulk-seq analysis showed that these aggrephagy-related subclusters had significant predictive value for the survival and immune checkpoint blockade response in EC patients. Notably, immunohistochemical staining results manifested that the TUBA1A+ macrophage subtype was linked to less lymph node metastasis and longer survival, which were consistent with the bioinformatics analysis findings.ConclusionsThis study provided a novel view of aggrephagy signaling in the EC tumor microenvironment, and intervention of aggrephagy was expected to improve the survival rate of EC patients.

Pan-cancer analysis of co-inhibitory molecules revealing their potential prognostic and clinical values in immunotherapy

BackgroundThe widespread use of immune checkpoint inhibitors (anti-CTLA4 or PD-1) has opened a new chapter in tumor immunotherapy by providing long-term remission for patients. Unfortunately, however, these agents are not universally available and only a minority of patients respond to them. Therefore, there is an urgent need to develop novel therapeutic strategies targeting other co-inhibitory molecules. However, comprehensive information on the expression and prognostic value of co-inhibitory molecules, including co-inhibitory receptors and their ligands, in different cancers is not yet available.MethodsWe investigated the expression, correlation, and prognostic value of co-inhibitory molecules in different cancer types based on TCGA, UCSC Xena, TIMER, CellMiner datasets. We also examined the associations between the expression of these molecules and the extent of immune cell infiltration. Besides, we conducted a more in-depth study of VISTA. ResultThe results of differential expression analysis, correlation analysis, and drug sensitivity analysis suggest that CTLA4, PD-1, TIGIT, LAG3, TIM3, NRP1, VISTA, CD80, CD86, PD-L1, PD-L2, PVR, PVRL2, FGL1, LGALS9, HMGB1, SEMA4A, and VEGFA are associated with tumor prognosis and immune cell infiltration. Therefore, we believe that they are hopefully to serve as prognostic biomarkers for certain cancers. In addition, our analysis indicates that VISTA plays a complex role and its expression is related to TMB, MSI, cancer cell stemness, DNA/RNA methylation, and drug sensitivity.ConclusionsThese co-inhibitory molecules have the potential to serve as prognostic biomarkers and therapeutic targets for a broad spectrum of cancers, given their strong associations with key clinical metrics. Furthermore, the analysis results indicate that VISTA may represent a promising target for cancer therapy.

Gastrointestinal tumors of the small bowel: prognostic roles of tumor stage and inflammatory markers

Aims: Small bowel tumors are a heterogeneous group of malignancies, including gastrointestinal stromal tumors (GISTs), adenocarcinomas, neuroendocrine tumors (NETs), and myofibroblastic tumors, each with distinct prognostic implications. While tumor stage is a well-established prognostic factor, patient survival outcomes and systemic inflammatory markers also play a crucial role in disease progression. This study evaluates these factors comprehensively to enhance prognostic assessment in small bowel malignancies. Methods: This retrospective study analyzed 25 patients diagnosed with small bowel tumors, including various histological subtypes. The prognostic significance of tumor stage (T and N classification), systemic inflammatory markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], albumin, and C-reactive protein [CRP]), and overall survival was assessed. Kaplan-Meier survival analysis was conducted to evaluate the association between tumor stage, inflammatory markers, and patient outcomes. Statistical analyses included independent sample t-tests, Mann-Whitney U tests, and Chi-square tests. Results: The median age of the cohort was 63 years (range: 47–81). The most common histological subtype was GIST (52%), followed by adenocarcinoma (24%), NET (20%), and myofibroblastic tumors (4%). Kaplan-Meier survival analysis revealed a significant association between tumor stage and patient survival (p=0.036), with advanced-stage tumors (T3–T4) demonstrating significantly lower survival rates compared to early-stage tumors (T2). Lymph node involvement (N stage) was also a significant predictor of reduced survival (p=0.013). Although inflammatory markers such as NLR, PLR, albumin, and CRP were assessed, they did not show statistically significant associations with survival outcomes (p>0.05). Conclusion: This study highlights the importance of evaluating both tumor stage and patient survival when determining prognosis in small bowel tumors. The Kaplan-Meier analysis underscores the strong prognostic impact of tumor staging and lymph node involvement on survival outcomes. Although systemic inflammatory markers did not show significant prognostic value in this cohort, their role in risk stratification warrants further investigation in larger studies. These findings contribute to a broader understanding of small bowel tumor prognosis beyond staging alone, supporting the need for a multidimensional approach in clinical assessment and treatment planning.

Tumor Microenvironment Dynamics of Triple-Negative Breast Cancer Under Radiation Therapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. While TNBC is relatively less common, accounting for only 10-15% of initial breast cancer diagnosis, due to its aggressive nature, it carries a worse prognosis in comparison to its hormone receptor-positive counterparts. Despite significant advancements in the screening, diagnosis, and treatment of breast cancer, TNBC remains an important public health burden. Following treatment with chemotherapy, surgery, and radiation, over 40% of TNBC patients experience relapse within 3 years and achieve the least benefit from post-mastectomy radiation. The tumor microenvironment environment (TME) is pivotal in TNBC initiation, progression, immune evasion, treatment resistance, and tumor prognosis. TME is a complex network that consists of immune cells, non-immune cells, and soluble factors located in the region adjacent to the tumor that modulates the therapeutic response differentially between hormone receptor-positive breast cancer and TNBC. While the mechanisms underlying the radiation resistance of TNBC remain unclear, the immunosuppressive TME of TNBC has been implicated in chemotherapeutic resistance. Radiation therapy (RT) is known to alter the TME; however, immune changes elicited by radiation are poorly characterized to date, and whether these immune changes contribute to radiation resistance remains unknown. This review delves into the distinct characteristics of the TNBC TME, explores how RT influences TME dynamics, and examines mechanisms underlying tumor radiosensitization, radioresistance, and immune responses.

Exploring the Potential of Optical Genome Mapping in the Diagnosis and Prognosis of Soft Tissue and Bone Tumors.

Sarcomas are rare malignant tumors of mesenchymal origin with a high misdiagnosis rate due to their heterogeneity and low incidence. Conventional diagnostic techniques, such as Fluorescence In Situ Hybridization (FISH) and Next-Generation Sequencing (NGS), have limitations in detecting structural variations (SVs), copy number variations (CNVs), and predicting clinical behavior. Optical genome mapping (OGM) provides high-resolution genome-wide analysis, improving sarcoma diagnosis and prognosis assessment. This study analyzed 53 sarcoma samples using OGM. Ultra-high molecular weight (UHMW) DNA was extracted from core and resection biopsies, and data acquisition was performed with the Bionano Saphyr platform. Bioinformatic pipelines identified structural variations, comparing them with known alterations for each sarcoma subtype. OGM successfully analyzed 62.3% of samples. Diagnostic-defining alterations were found in 95.2% of cases, refining diagnoses and revealing novel oncogenic and tumor suppressor gene alterations. The challenges included DNA extraction and quality issues from some tissue samples. Despite these limitations, OGM proved to be a powerful diagnostic and predictive tool for bone and soft tissue sarcomas, surpassing conventional methods in resolution and scope, enhancing the understanding of sarcoma genetics, and enabling better patient stratification and personalized therapies.

Optimization of Immunotherapy Strategies Based on Spatiotemporal Heterogeneity of Tumour-Associated Tissue-Resident Memory T Cells.

Tissue-resident memory T cells (TRMs) reside in peripheral tissues and provide rapid immune defence against local infection and tumours. Tumour-associated TRMs share common tissue-resident features and formation mechanisms, representing some unique subsets of tumour-infiltrating lymphocytes (TILs). However, differences in the tumour microenvironment(TME) and tumour evolution stage result in TRMs exhibiting temporal and spatial heterogeneity of phenotype and function not only at different stages, before and after treatment, but also between tumours originating from different tissues, primary and metastatic cancer, and tumour and adjacent normal tissue. The infiltration of TRMs is often associated with immunotherapy response and favourable prognosis; however, due to different definitions, it has been shown that some subtypes of TRMs can also have a negative impact. Therefore, it is crucial to precisely characterise the TRM subpopulations that can influence the therapeutic efficacy and clinical prognosis of various solid tumours. Here, we review the spatiotemporal heterogeneity of tumour-associated TRMs, as well as the differences in their impact on clinical outcomes. We also explore the relationship between TRMs and immune checkpoint blockade (ICB) and TIL therapy, providing insights into potential new targets and strategies for immunotherapy.

Operative management and outcomes of testicular tumors in children: a 10-year multicentric Egyptian experience

BackgroundThis national study highlights the surgical management and outcomes of pediatric testicular tumors to evaluate our treatment approaches. All male patients younger than 18 years diagnosed with primary testicular tumors and treated at six Egyptian surgical units from 2014 to 2024 were included. Data were analyzed regarding clinical characteristics, operative details, adjuvant therapy, pathological variants, and overall outcomes.ResultsThe study included 36 patients with a median age of 3.5 years (range: 12 days-17 years). Twenty-six patients (72%) were prepubertal, while 10 (28%) were postpubertal. Benign lesions were observed in 21 patients (58%), while 15 patients (42%) had malignant tumors. Four patients had metastatic disease at diagnosis, and all of them were postpubertal. Twenty-seven patients underwent radical high inguinal orchiectomy, whereas testicular-sparing surgery (TSS) was performed in 9 patients (25%). All patients who underwent TSS were prepubertal and had negative serum tumor markers. According to Children's Oncology Group staging system, 32 patients (89%) were classified as stage I, three patients as stage III, and one patient as stage IV. The four patients with stage III and IV disease received adjuvant chemotherapy, and two of them underwent retroperitoneal lymph node dissection to resect residual para-aortic/iliac nodes. One patient with stage III seminoma developed distant relapse after 20 months of remission, which was controlled with intensive chemotherapy. At a median follow-up of 58 months, all patients were still alive. The 5-year overall and event-free survival rates for all patients were 100% and 96%, respectively.ConclusionsRadical orchiectomy is still performed for many patients due to insufficient remaining testicular parenchyma. TSS is highly recommended whenever feasible for prepubertal patients with benign-appearing tumors and sufficient healthy testicular tissue. The prognosis for pediatric testicular tumors is generally excellent across various age groups and pathological types. However, malignant tumors with metastases may be associated with less favorable outcomes.

The Role of Coagulation-Related Genes in Glioblastoma: A Comprehensive Analysis of the Tumor Microenvironment, Prognosis, and Treatment.

The influence of coagulation on glioma biology has not been comprehensively elucidated. This study explores the role of coagulation-related genes (CRGs) in glioblastoma (GBM) from the perspectives of the tumor microenvironment (TME), differences in coagulation function among GBM patients, treatment, and prognosis. Somatic mutation analysis was performed on single nucleotide polymorphism (SNP) and copy number variation data from GBM patients in the TCGA cohort. Publicly available single-cell RNA sequencing data were used to analyze the role of coagulation in the GBM TME and its underlying biological mechanisms. Unsupervised clustering of GBM patients from the CGGA693 cohort was conducted, and coagulation function for each patient was assessed using ssGSEA scoring. Prognosis was assessed with Kaplan-Meier survival analysis, and immune infiltration was analyzed through ESTIMATE. A risk signature based on five CRGs (CFI, GNG12, MMP2, LEFTY2, and SERPINC1) was constructed and validated using LASSO regression and random survival forest analyses to predict responses to immunotherapy and identify potential sensitive drugs. Finally, the roles of LEFTY2 and SERPINC1 in GBM progression was verified by immunohistochemistry, cell counting kit-8 (CCK8) assay and wound healing assay, and the anti-GBM effect of the drug PLX4720 was verified by CCK8 assay, wound healing assay, and colony formation assay. Somatic mutation analysis revealed SNP events of CRG mutations in 117 out of 461 GBM cases (25.38%). Single-cell analysis of the GBM TME revealed significant activation of the coagulation pathway in endothelial cells, with intercellular communication mediated via the SPP1-integrin pathway (p < 0.01). Clustering analysis and ssGSEA identified two coagulation-related subtypes in GBM: coagulation-activated and coagulation-inhibited subtypes. Patients in the coagulation-activated subtype exhibited shorter overall survival and poorer prognosis compared to those in the coagulation-inhibited subtype (p = 0.0085). Immune infiltration analysis showed lower tumor purity and higher levels of immune-suppressive cells in the coagulation-activated subtype (p < 0.001). The CRG-based risk signature accurately predicted prognosis (p < 0.0001) and responses to immunotherapy in the IMvigor210 cohort (p = 0.0062). Based on the risk model, PLX4720 was identified as a potential sensitive drug (p < 0.001), and drug validation experiments demonstrated that PLX4720 inhibited the proliferation and migration of glioma cells (p < 0.0001). In vitro experiments demonstrated that LEFTY2 and SERPINC1 were significantly overexpressed in GBM compared to normal brain tissue, and knockdown of LEFTY2 and SERPINC1 inhibited glioma cell proliferation and migration (p < 0.05). The CRG-based risk signature model effectively predicts the prognosis of GBM patients and aids in assessing the efficacy of ICI therapy and chemotherapy. Furthermore, the genes LEFTY2, SERPINC1 and the drug PLX4720 offer potential directions for the development of novel therapeutic strategies for GBM.

O8G-modified circPLCE1 inhibits lung cancer progression via chaperone-mediated autophagy

BackgroundLung cancer poses a serious threat to human health, but its molecular mechanisms remain unclear. Circular RNAs (circRNAs) are closely associated with tumour progression, and the important role of 8-oxoguanine (o8G) modification in regulating the fate of RNA has been gradually revealed. However, o8G modification of circRNAs has not been reported. We identified circPLCE1, which is significantly downregulated in lung cancer, and further investigated the o8G modification of circPLCE1 and the related mechanism in lung cancer progression.MethodsWe identified differentially expressed circRNAs by RNA high-throughput sequencing and then conducted methylated RNA immunoprecipitation (MeRIP), immunofluorescence (IF) analysis, crosslinking immunoprecipitation (CLIP) and actinomycin D (ActD) assays to explore circPLCE1 o8G modification. The biological functions of circPLCE1 in vivo and in vitro were clarified via establishing a circPLCE1 silencing/overexpression system. Tagged RNA affinity purification (TRAP), RNA Immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays, and pSIN-PAmCherry-KFERQ-NE reporter gene were used to elucidate the molecular mechanism by which circPLCE1 inhibits lung cancer progression.ResultsThis study revealed that reactive oxygen species (ROS) can induce circPLCE1 o8G modification and that AUF1 can mediate a decrease in circPLCE1 stability. We found that circPLCE1 significantly inhibited lung cancer progression in vitro and in vivo and that its expression was associated with tumour stage and prognosis. The molecular mechanism was elucidated: circPLCE1 targets the HSC70 protein, increases its ubiquitination level, regulates ATG5-dependent macroautophagy via the chaperone-mediated autophagy (CMA) pathway, and ultimately inhibits lung cancer progression.Conclusiono8G-modified circPLCE1 inhibits lung cancer progression through CMA to inhibit macroautophagy and alter cell fate. This study provides not only a new theoretical basis for elucidating the molecular mechanism of lung cancer progression but also potential targets for lung cancer treatment.Graphical abstractROS induce circPLCE1 o8G modification, and AUF1 specifically recognizes o8G modification, thereby decreases circPLCE1 stability. circPLCE1 targets the HSC70 protein, increases its ubiquitination level, inhibits CMA activity, and promotes ATG5-dependent macroautophagy via the CMA pathway, altering the fate of tumour cells and ultimately inhibiting lung cancer progression.

A pan-cancer analysis reveals the oncogenic and immunological role of insulin-like growth factor 2 mRNA-binding protein family members

PurposeTo investigate the expression and clinical significance of insulin-like growth factor 2 mRNA-binding protein family members (IGF2BPs) in pan-cancer and evaluate their potential as targets for tumor immunotherapy.MethodsBased on data from the cancer genome atlas (TCGA) database, pan-cancer analysis was conducted to examine the clinical significance of IGF2BPs expression in twenty-two tumors.ResultsDifferential expression analysis showed high expression of IGF2BPs in most tumor tissues. Survival and mutation analyses suggested that the overexpression of IGF2BPs was associated with poor prognosis and mutation status of certain tumors. Methylation analysis revealed the methylation levels of IGF2BP1/2/3 in certain tumors were intricately linked to their mRNA expression, patient prognosis, and immune cell infiltration. Enrichment analysis indicated that abnormal expression of IGF2BPs was associated with various common tumor-related pathways in different tumors, including AMPK, Hippo, PI3K-Akt, EMT, and p53. In addition, immune correlation analysis revealed that IGF2BPs were closely related to immunotherapy-related indicators (immune cell infiltration, major histocompatibility complex (MHC), immune checkpoints, tumor mutation burden (TMB), and microsatellite instability (MSI)) in some tumors. Drug sensitivity analysis indicated that IGF2BPs were sensitive to some common chemotherapeutic drugs (alvocidib, dasatinib, trametinib, and selumetinib).ConclusionIGF2BPs exhibit significantly high expression in most tumors and are associated with prognosis, pathological stage, mutational status, methylation levels, and the relevant indicators of immunotherapy sensitivity in multiple tumors. Moreover, IGF2BPs may play an oncogenic role by activating common signaling pathways. Therefore, IGF2BPs may be potential prognostic markers for tumor therapy and targets for immunotherapy and drug therapy.

Research and analysis of circulating tumor cell detection in the diagnosis and treatment of gastric cancer.

Circulating tumor cells (CTCs) are crucial for improving our knowledge regarding tumor progress, prognosis, and recurrence possibility. To evaluate the role of CTCs in the early diagnosis and treatment of gastric cancer. From June 2020 to December 2021, a randomized study was conducted in our institution involving 80 patients scheduled for surgery for gastric cancer. The patients were divided into two groups: A control group that was tested for traditional serum markers and a study group that was assessed for serum CTCs. In the study cohort, CTC levels did not correlate significantly with patient age, gender, or degree of tumor differentiation (P > 0.05). However, there was a significant correlation with the tumor-node-metastasis stage of the tumor (P < 0.05). In the study group, the CTC diagnostic positivity rate was 62.50% (25 out of 40 patients), while the positivity rate for conventional serum markers in the control group was 47.50% (19 out of 40 patients). The positive detection rate in the study group was significantly higher than that of the control group (P < 0.05). CTCs have slight invasion and high sensitivity and specificity, presenting great value for early clinical diagnosis of recurrence and metastasis. It will improve the deceleration of disease development and increase the survival rate.

Correlation between tumor stroma ratio, prognosis, and apparent diffusion coefficient in alveolar soft part sarcoma.

To investigate the correlation between tumor stroma ratio (TSR) and survival in patients with alveolar soft part sarcoma (ASPS), and the application of apparent diffusion coefficient (ADC) histogram parameters in assessing TSR. This retrospective study collected 61 patients from May 2015 to December 2018. TSR was classified as stroma-rich (low TSR) or stroma-poor (high TSR) based on histology. The correlation between TSR and clinicopathological characteristics was analyzed. Prognostic value for 5-year progression-free survival (5-PFS) and 5-year overall survival (5-OS) were assessed using Kaplan-Meier analysis, log-rank test, and Cox regression. Independent sample t-tests or Mann-Whitney U-test and receiver operating characteristic curve analysis examined TSR and ADC histogram parameters. Sixty-one patients met the inclusion criteria (mean age 25.5 ± 12.2 years; 30 males, 31 females). Low TSR was significantly associated with lymph node metastasis (p = 0.048). In multivariate analysis, low TSR was an independent adverse prognostic factor for 5-PFS (hazard ratios [HR] and 95% = 10.456, 95% confidence intervals [CI]: 1.816-60.208, p = 0.009) and 5-OS (HR = 4.789, 95% CI: 1.164-19.708, p = 0.030). Significant differences were found in ADC25th, ADC50th, and ADCmean between TSR groups (p < 0.05). The combination of the three ADC values improved diagnostic efficiency (area under the curve = 0.781, sensitivity = 81.48%, specificity = 82.35%), with a Youden index of 0.638. TSR is an independent prognostic factor for PFS and OS in ASPS patients. ADC histogram parameters serve as imaging biomarkers for evaluating TSR. Question The prognostic value of TSR in ASPS remains unclear, with limited imaging biomarkers available for assessment. Findings Low TSR is associated with poorer 5-PFS and OS. ADC histogram parameters aid in TSR evaluation. Clinical relevance TSR as a prognostic factor, assessed through ADC histogram parameters, offers a non-invasive imaging method that may be useful in predicting the progression of alveolar soft tissue sarcoma.

Cancer-associated fibroblast heterogeneity in chordoma†.

In solid tumours, malignant cells develop relationships with nonmalignant stromal cells to support tumour growth, tissue structure, and nutrient supply. In a recent issue of this journal, Zheng and Guo catalogue the cellular landscape in chordoma using a combination of single-cell and spatial transcriptomics. Despite the mesenchymal nature of chordoma, malignant cells retain expression of epithelial markers, in addition to mesenchymal, partial-EMT, and stem-cell signatures. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells and the authors define an inflammatory CAF subtype (iCAF), which is associated with poor outcome and tumour invasion. It is proposed that iCAFs arise from normal fibroblasts during malignant tumour progression and play a causative role in driving an invasive poor prognosis tumour phenotype. Recent reports by this and other groups have separately catalogued cell populations, including CAFs and immune cells in chordoma. The next challenge will be to integrate findings from these distinct studies to allow a consensus to be reached regarding cellular heterogeneity within chordoma, and to allow comparison of CAF populations with those found in other tumour types. Comparison of CAF functions in these predominantly mesenchymal tumours with epithelial solid tumours may reveal interesting lessons about the diverse phenotypes CAFs can bring to distinct tumour ecosystems. Understanding the role of CAFs in chordoma progression may also lead to therapeutic opportunities, but separation of correlation and causation in CAF regulation of tumour phenotypes remains a significant challenge. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Escape from TGF-β-induced senescence promotes aggressive hallmarks in epithelial hepatocellular carcinoma cells.

Transforming growth factor-β (TGF-β) signaling and cellular senescence are key hallmarks of hepatocellular carcinoma (HCC) pathogenesis. Despite provoking senescence-associated growth arrest in epithelial HCC cells, elevated TGF-β activity paradoxically correlates with increased aggressiveness and poor prognosis in advanced tumors. Whether the transition between these dichotomous functions involves modulation of the senescence phenotype during disease progression remains elusive. Exploiting the epithelial HCC cell line Huh7 as a robust model, we demonstrate that chronic exposure to TGF-β prompts escape from Smad3-mediated senescence, leading to the development of TGF-β resistance. This altered state is characterized by an optimal proliferation rate and the acquisition of molecular and functional traits of less-differentiated mesenchymal cells, coinciding with differential growth capacity in 2D and 3D culture conditions, epithelial-to-mesenchymal transition (EMT), and increased invasiveness in vitro, and metastasis in vivo. Mechanistically, resistant cells exhibit defective activation and nuclear trafficking of Smad molecules, particularly Smad3, as ectopic activation of the TGF-β/Smad3 axis is able to reinstate TGF-β sensitivity. An integrated transcriptomic landscape reveals both shared and distinct gene signatures associated with senescent and TGF-β resistant states. Importantly, genetic ablation and molecular studies identify microtubule affinity regulating kinase 1 (MARK1) and glutamate metabotropic receptor 8 (GRM8) as critical modulators of the resistance phenomenon, potentially by impairing spatiotemporal signaling dynamics of Smad activity. Our findings unveil a novel phenomenon wherein epithelial HCC cells may exploit senescence plasticity as a mechanism to oppose TGF-β anti-tumor responses and progress towards more aggressive HCC phenotypes.

Identification of TAP2 as a novel immune target in human cancers: insights from integrated bioinformatics and experimental approaches

BackgroundTransporter 2, ATP binding cassette (ABC) subfamily B member (TAP2), encodes a protein within the ABC transporter superfamily. TAP2 plays a role in the progression of cancers, such as cervical, breast, and lung cancers. However, the relationship between TAP2 and cancer prognosis, immune cell infiltration, tumor microenvironment, and immunotherapy remains unexplored. Therefore, this study aims to investigate the effect of TAP2 expression on its role in predicting tumor prognosis and immunotherapy efficacy.MethodsBioinformatics analyses such as Gene Set Enrichment Analysis, single-cell, and Connectivity Map analyses were used to comprehensively assess TAP2-related genomic alterations, prognostic value, enrichment pathways, single-cell expression patterns, and potential targeting inhibitors. In addition, molecular docking techniques were used to simulate drug binding to TAP2. WB and RT-qPCR were used to detect differences in TAP2 expression in glioma cell lines. The U251MG cell line was established with TAP2 overexpression. The effects of elevated TAP2 expression on GBM cell function was evaluated using various assays, including the Transwell migration, scratch, and clonal formation assays.ResultsTAP2 exhibited aberrantly expression in tumor tissues with genomic alterations. TAP2 significantly correlates with poor prognosis across various cancers. It was also involved in immune-related pathways, immune infiltration, and immune checkpoint regulation, thereby influencing the tumor microenvironment and immune response to cancer. TAP2 was identified as a potential predictor of immunotherapy response and screened for potential targeted inhibitors for future therapeutic interventions.ConclusionsOur findings suggest that TAP2 may serve as a promising prognostic marker and immune target in human cancers, warranting further investigation into its role in tumor immunity.

Leveraging microbiome signatures to predict tumor immune microenvironment and prognosis of patients with endometrial carcinoma

Recent studies suggest that the human microbiome influence tumor development. Endometrial carcinoma (EC) is the sixth most common malignancy in women. Recent research has demonstrated the microbes play a critical role in the development and metastasis of EC. However, it remains unclear whether intratumoral microbes are associated with tumor microenvironment (TME) and prognosis of EC. In this study, we collected the EC microbiome data from cBioPortal and constructed a prognostic model based on Resident Microbiome of Endometrium (RME). We then examined the relationship between the RME score, immune cell infiltration, immunotherapy-related signature, and prognosis. The findings demonstrated the independent prognostic value of the RME score for EC. The group with low RME scores had higher enrichment of immune cells. Drug sensitivity analysis revealed that the RME score may serve as a potential predictor of chemotherapy efficacy. In conclusion, our research offers new perspectives on the relationships between tumor immunity and microbes.

The correlation between epithelial-mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma.

Epithelial-mesenchymal transition (EMT) and circulating tumor cells (CTCs) are key prognostic factors in nasopharyngeal carcinoma (NPC). However, the role of EMT status in CTCs for predicting outcomes in advanced NPC treated with radiotherapy after induction chemotherapy remains unclear. A total of 143 CTC tests from 95 advanced/metastatic NPC patients were analyzed before, during, and after radiotherapy, with a 60-month follow-up. CTC count, matrix metalloproteinase 2 (MMP2)) protein expression, and EMT subtypes were examined. During radiotherapy, CTC counts increase but decrease afterward. Patients with higher pre-radiotherapy tumor-node-metastasis (TNM) stages have lower total and M-subtype CTC counts. Higher T and TNM stages during radiotherapy correlate with increased EMT-state CTCs, especially hybrid CTCs. EA/IgG-positive patients have a higher number of hybrid CTCs and E-type (epithelial + hybrid) CTCs, while EBV-EA-negative patients have more mesenchymal CTCs. A higher post-radiotherapy CTC count predicts relapse, and the positive rate of MMP2 expression on hybrid and epithelial CTCs is higher than that on mesenchymal CTCs. EMT status, particularly in hybrid CTCs, is a potential prognostic marker for relapse in advanced NPC after radiotherapy.

The Biology in the Pattern: Metastatic organotropism and clinical outcome depend on DNA damage response and immune interactions in pancreatic cancer.

Metastatic cancer remains a leading cause of cancer-related mortality, with a 5-year survival rate of just 8% for pancreatic ductal adenocarcinoma (PDAC). Among patients with metastatic PDAC, those with liver metastases experience significantly worse outcomes compared to the rare cases of isolated lung metastases. Recent findings by Link and colleagues reveal that these distinct metastatic patterns reflect underlying biological differences beyond established molecular subtypes. Specifically, the authors curated a primary organotropism (pORG) gene signature that is enriched in the liver cohorts. In detail they found that high-pORG/liver-avid tumors are characterized by high replication stress, enriched DNA repair pathways, and an immunosuppressive microenvironment, whereas low-pORG/lung-avid tumors display stronger immune infiltration, higher T cell density and reduce the richness of TCR repertoire, and better survival outcomes. These insights suggest that the clinical pattern of metastasis provides meaningful information about tumor biology and prognosis, complementing current subtype classifications in PDAC.