Cellular Oncology最新文献

Purpose: P-cadherin (CDH3) is a transmembrane protein that plays a crucial role in maintaining the structural integrity of epithelial tissue and homeostasis. Its role in carcinogenesis remains a subject of debate, as its behavior can vary depending on the molecular context and the specific tumor cell model under study. In this study, we explored the role of P-cadherin in head and neck squamous cell carcinoma (HNSCC) and the mechanisms underlying its function.

Methods: We analyzed P-cadherin expression in HNSCC patients using The Cancer Genome Atlas (TCGA), The Chungnam National University Hospital (CNUH) cohort and Gene Expression Omnibus (GEO) database. For in vitro functional analysis, we conducted proliferation, migration, invasion, and western blot assays after either suppressing or overexpressing P-cadherin. For in vivo functional analysis, we utilized mouse xenograft models.

Results: P-cadherin was significantly overexpressed in tumor samples compared to normal samples in the TCGA-HNSCC and CNUH-HNSCC cohorts. P-cadherin knockdown resulted in decreased proliferation, migration, and invasion compared to control cells, while P-cadherin overexpression increased cell proliferation and migration in HNSCC cells. We discovered that c-Met functions as an upstream regulator of P-cadherin. Surprisingly, we found that P-cadherin knockdown increased the phosphorylation of c-Met and STAT3. Combining P-cadherin siRNA with the c-Met inhibitor SU11274 or c-Met siRNA resulted in a more effective reduction in HNSCC cell growth, both in vitro and in vivo, compared to either treatment alone.

Conclusion: Our study uncovered a previously unknown aspect of P-cadherin-mediated c-Met regulation. The enhanced activation of c-Met/STAT3 following P-cadherin inhibition could be responsible for the survival of resistant tumor cells. Therefore, dual inhibition of P-cadherin and c-Met may be an effective approach for treating HNSCC.

The relationship between bacterial activity and tumorigenesis has gained attention in recent years, complementing the well-established association between viruses and cancer. A recent study employed immunodetection of lipopolysaccharide (LPS) to demonstrate the presence of intracellular bacteria within cancer cells across various cancer types, including breast cancer. The authors proposed that these bacteria might play a role in tumor development. We sought to replicate these findings using the same experimental methods on an independent cohort of breast cancer cases. Our analysis of 129 samples revealed no evidence of LPS expression within cancer cells. Instead, LPS immunoreactivity was observed in ducts or immune cells, specifically macrophages, as expected. These discrepancies in LPS immunodetection warrant caution in interpreting the original findings, and further research is needed to clarify the potential role of intracellular bacteria in cancer development.

Metastasis, the leading cause of cancer-related deaths, underscores the critical need to understand its regulatory mechanisms to improve prevention and treatment strategies for late-stage tumors. Hematogenous dissemination is a key route of metastasis. However, as the gatekeeper of vessels, the role of pericytes in hematogenous metastasis remains largely unknown. In this review, we comprehensively explore the contributions of pericytes throughout the metastatic cascade, particularly their functions that extend beyond influencing tumor angiogenesis. Pericytes should not be perceived as passive bystanders, but rather as active participants in various stages of the metastatic cascade. Pericytes-targeted therapy may provide novel insights for preventing and treating advanced-stage tumor.

Purpose: Although 60-70% of diffuse large B-cell lymphoma (DLBCL) patients can be cured with the current standard of chemotherapy and immunotherapy, the remaining patients experience treatment resistance and have poor clinical outcomes. More effective strategies are needed for the DLBCL treatment.

Methods: Databases of clinical patients were analyzed to investigate potential functions of leukocyte immunoglobulin-like receptor B1 (LILRB1) in DLBCL. Short hairpin RNAs were used for validation of in vitro and in vivo function of LILRB1 in DLBCL. RNA-seq was applied to explore potential mechanism, western blot and chromatin immunoprecipitation techniques were used to characterize the underlying signaling of CREB-SORBS3 pathway.

Results: We found that LILRB1 was highly expressed in DLBCL cells and was adversely correlated with the overall survival of DLBCL patients. Knockdown of LILRB1 effectively inhibited the proliferation of DLBCL cells both in vitro and in vivo. Mechanistically, LILRB1 upregulated CREB/CREB phosphorylation and transactivated SORBS3 expression to maintain DLBCL cell proliferation and tumorigenicity.

Conclusion: In this work, we revealed that LILRB1 was highly expressed in DLBCL cells and was negatively correlated with patient survival. Furthermore, we found that the LILRB1-CREB-SORBS3 pathway played a role in maintaining the proliferation of DLBCL cells. These data suggest that LILRB1 might be a potential target for the treatment of DLBCL.

Purpose: Immunotherapy has transformed the neoadjuvant treatment landscape for patients with resectable locally advanced non-small cell lung cancer (NSCLC). However, a population of patients cannot obtain major pathologic response (MPR) and thus benefit less from neoadjuvant immunotherapy, highlighting the need to uncover the underlying mechanisms driving resistance to immunotherapy.

Methods: Two published single-cell RNA sequencing (scRNA-seq) datasets were used to analyze the subsets of cancer-associated fibroblasts (CAFs) and T cells and functional alterations after neoadjuvant immunotherapy. The stromal signature predicting ICI response was identified and validated using our local cohort with stage III NSCLC receiving neoadjuvant immunotherapy and other 4 public ICI transcriptomic cohorts.

Results: Non-MPR tumors showed higher enrichment of CAFs and increased extracellular matrix deposition than MPR tumors, as suggested by bioinformatic analysis. Further, CAF-mediated immune suppression may involve reciprocal interactions with T cells in addition to a physical barrier mechanism. In contrast, MPR tumors demonstrated therapy-induced activation of memory CD8⁺ T cells into an effector phenotype. Additionally, neoadjuvant immunotherapy resulted in expansion of precursor exhausted T (Texp) cells, which were remodeled into an anti-tumor phenotype. Notably, we identified metabolic heterogeneity within distinct T cell clusters during immunotherapy. Methionine recycling emerged as a predictive factor for T-cell differentiation and a favorable pathological response. The stromal signature was associated with ICI response, and this association was validated in five independent ICI transcriptomic cohorts.

Conclusion: These discoveries underscore the distinct tumor microenvironments in MPR and non-MPR patients and may elucidate resistance mechanisms to immunotherapy in NSCLC.

A substance integral to the sustenance and functionality of virtually all forms of life is manganese (Mn), classified as an essential trace metal. Its significance lies in its pivotal role in facilitating metabolic processes crucial for survival. Additionally, Mn exerts influence over various biological functions including bone formation and maintenance, as well as regulation within systems governing immunity, nervous signaling, and digestion. Manganese nanoparticles (Mn-NP) stand out as a beacon of promise within the realm of immunotherapy, their focus honed on intricate mechanisms such as triggering immune pathways, igniting inflammasomes, inducing immunogenic cell death (ICD), and sculpting the nuances of the tumor microenvironment. These minuscule marvels have dazzled researchers with their potential in reshaping the landscape of cancer immunotherapy - serving as potent vaccine enhancers, efficient drug couriers, and formidable allies when paired with immune checkpoint inhibitors (ICIs) or cutting-edge photodynamic/photothermal therapies. Herein, we aim to provide a comprehensive review of recent advances in the application of Mn and Mn-NP in the immunotherapy of cancer. We hope that this review will display an insightful view of Mn-NPs and provide guidance for design and application of them in immune-based cancer therapies.

Purpose: Gastric cancer (GC) remains a considerable global health concern, underscoring the necessity for dependable biomarkers for its diagnosis and treatment. This investigation seeks to investigate the clinical predictive value and functional roles of SPTSSA in GC.

Methods: The mRNA expression of SPT family molecules was analyzed through bioinformatics approaches. In vitro and in vivo studies assessed the function of SPTSSA in the malignant progression of GC. Additionally, SPTSSA protein levels in GC tissues and peripheral venous blood were measured using immunofluorescence staining and enzyme-linked immunosorbent assay, respectively. The link between SPTSSA expression and immune cell infiltration in GC was also evaluated by multiplex immunohistochemistry.

Results: Patients exhibiting elevated levels of SPTSSA mRNA experienced the poorest prognosis in comparison to other members of the SPT family. SPTSSA overexpression enhanced the malignant phenotype of GC in in vitro and in vivo experiments. Mechanistically, SPTSSA facilitated the accumulation of β-catenin and the transcription of programmed death ligand 1 (PD-L1) through the Wnt signaling pathway. SPTSSA protein levels were markedly elevated in both GC tissues and peripheral venous blood. Furthermore, increased expression of SPTSSA was linked to a reduction in CD8⁺ T cell infiltration, heightened M2 macrophage infiltration, and increased PD-L1 expression in GC patients.

Conclusion: SPTSSA promotes GC progression by modulating PD-L1 expression in immunomicroenvironment via the Wnt signaling pathway. Consequently, SPTSSA emerges as a promising new prognostic indicator and a potential therapeutic target for GC management.

Purpose: Post-translational modifications, such as lactylation, are emerging as critical regulators of metabolic enzymes in cancer progression. Mitochondrial malic enzyme 2 (ME2), a key enzyme in the TCA cycle, plays a pivotal role in maintaining redox homeostasis and supporting tumor metabolism. However, the functional significance of ME2 lactylation and its regulatory mechanisms remain unclear. This study investigates the role of ME2 K352 lactylation in modulating enzymatic activity, redox balance, and tumor progression.

Methods: Immunoprecipitation and western blotting were used to assess ME2 lactylation and its interaction with Sirtuin 3 (SIRT3). Mass spectrometry identified the lactylation site on ME2. Enzymatic activity was measured using NADH production assays. The functional effects of ME2 K352 lactylation were analyzed by measuring ROS levels, NADP⁺/NADPH ratios, metabolic intermediates, and mitochondrial respiration parameters. Cell proliferation was evaluated via CCK-8 and colony formation assays. Xenograft tumor models and Ki-67 immunohistochemical staining were used to assess tumor growth and proliferation in vivo.

Results: Mass spectrometry identified K352 as the primary lactylation site on ME2. Sodium lactate treatment enhanced ME2 lactylation and enzymatic activity, while SIRT3-mediated delactylation at K352 reduced ME2 activity, disrupting redox homeostasis. Cells expressing the K352R mutant exhibited elevated ROS levels, higher NADP⁺/NADPH ratios, and altered levels of metabolic intermediates, including increased malate and lactate with reduced pyruvate. Additionally, re-expression of ME2 K352R in HCT116 cells significantly impaired proliferation and colony formation. In vivo, xenograft models demonstrated that ME2 K352R expression suppressed tumor growth, as evidenced by reduced tumor volume, weight, and Ki-67 staining.

Conclusions: This study reveals that ME2 K352 lactylation is a critical regulatory mechanism that modulates enzymatic activity, mitochondrial function, and tumor progression. SIRT3-mediated delactylation of ME2 K352 disrupts redox homeostasis and inhibits tumor growth. These findings highlight the potential of targeting ME2 lactylation as a therapeutic strategy in cancer treatment.

Purpose: There is a lack of clinical evidence on whether further clinical strategies are needed after TURBT combined with immediate bladder instillation. This study intends to establish a reliable quantitative assay for active urinary cancer cells (AUCC) and to investigate the clinical efficacy of continuous saline bladder irrigation (CSBI) as a feasible option by analyzing the perioperative AUCC changes in TURBT.

Methods: An AUCC assay was developed and its reliability was verified by single-cell whole genome sequencing. Bladder cancer patients (N = 324) diagnosed by cystoscopy and pathologic biopsy and control individuals (N = 92) were included from 2021 to 2023 in the study. Enrolled patients with non-muscle invasive bladder cancer (NMIBC) underwent TURBT followed by immediate bladder instillation of epirubicin, after subgroups received CSBI or not, and AUCCs were tested on the first and fifth postoperative day. The patients were followed up for two years for postoperative recurrence.

Results: The AUCC assay achieved good detection accuracy, with a sensitivity of 0.821 and specificity of 0.902. AUCC increased on the first day after TURBT in combination with immediate bladder instillation, regardless of whether or not the patient received CSBI. However, AUCCs decreased more rapidly on the fifth day in patients treated with CSBI, and patients with concomitant risk factors benefited more from CSBI. The two-year follow-up results showed that high-risk patients with complex surgeries could benefit significantly from CSBI.

Conclusions: We pioneered a quantitative assay for AUCC and provided laboratory evidence that TURBT causes tumor cell dissemination and CSBI can be a further clinical strategy to reduce the risk of potential recurrence.

Background: Non-small cell lung cancer (NSCLC) mainly includes lung squamous cell carcinoma and lung adenocarcinoma, and its extremely high morbidity and mortality are the main causes of poor prognosis in NSCLC patients. Therefore, it is particularly important to study the mechanisms associated with tumor proliferation and metastasis and explore new molecular targets of NSCLC. Studies have shown that Guanosine monophosphate synthase (GMPS) may serve as a potential drug target, but its biological function and molecular mechanism in NSCLC are still unknown. Therefore, it is urgently needed to investigate the molecular mechanisms of GMPS.

Methods: We first analyzed 30 cases of lung adenocarcinoma, lung squamous carcinoma and adjacent tissues; Then, lentiviral technology was used to construct overexpressed or knocked out cell lines to verify the function of GMPS. Then, RNA sequencing and Western blot experiments were carried out in animal experiments to explore the mechanism of GMPS. Our experimental results suggest that GMPS plays an important role in the progression of NSCLC.

Results: We found that GMPS was highly expressed in lung adenocarcinoma and lung squamous cell carcinoma tissues, and was associated with poor prognosis of patients. Down-regulation of GMPS inhibits tumor progression. And GMPS promotes lung cancer cell migration through the SERPINB2-uPA axis, and DNMT1 is an intermediate factor in GMPS regulating SERPINB2 expression. Our experimental results show that GMPS expression is associated with lung cancer invasion and migration.

Conclusions: Our findings revealed the correlation between GMPS and the prognosis of NSCLC at the tissue level. Secondly, GMPS can promote the progression of NSCLC. The molecular mechanism of GMPS affecting the metastasis of lung cancer cells was elucidated. These findings highlight the important role of GMPS in NSCLC, so as to provide new insights for the identification of new targets and lay a theoretical foundation for the clinical application of GMPS.