Translational cancer research最新文献

Background: For hormonal receptor-positive (HR⁺) breast cancer (BC), about 50% of recurrence occurs after 5-year adjuvant endocrine therapy (late recurrence). It is of great significance to identify the patients with a high risk of late recurrence who might benefit from extended endocrine therapy. This study aimed to construct a model predicting late recurrence of HR⁺/human epidermal growth factor receptor 2-negative (HER2^-) BC.

Methods: In this study, the female patients with HR⁺/HER2^- metastatic BC who were treated in the Department of Breast Oncology in Peking University Cancer Hospital were included. These patients were divided into the early recurrence group and the late recurrence group according to disease-free survival (DFS). Predictors for the recurrence time were identified and a nomogram was constructed and validated through concordance index (C-index), area under the curve (AUC), and calibration plots. The clinical data were collected from medical records.

Results: A total of 639 patients treated in the hospital between April 2007 and October 2019 were included. Median age of these patients at the initial diagnosis of primary tumors was 47 years old. Among them, 382 patients (59.8%) were presented with early recurrence (DFS ≤5 years), and 257 patients (40.2%) were presented with late recurrence (DFS >5 years). The median DFS was 50.0 months. Both univariate and multivariate analyses showed that a higher level of Ki-67 (P=0.005, 0.003) and more positive lymph nodes (P=0.003, 0.021) were associated with shorter DFS. A nomogram based on potentially associated clinicopathological factors was constructed and validation results showed that the nomogram was well-calibrated to predict the recurrence time of these patients (AUC =0.703, C-index =0.697).

Conclusions: A well-calibrated nomogram is constructed using the data of clinicopathological factors obtained from 639 HR⁺/HER2^- BC patients. Patients with premenopausal status at initial diagnosis, fewer positive lymph nodes and a lower level of Ki-67 were common factors for late recurrence. The nomogram could well predict the risk of late recurrence. Prospectively designed studies are needed to further validate the model.

Background: Small cell lung cancer (SCLC) is a subtype of lung cancer that is aggressive, progresses rapidly, and is prone to recurrence. The biological composition of SCLC is still under investigation. This study aims to characterize the intratumoral heterogeneity and immunosuppressive tumor microenvironment of SCLC using single-cell RNA sequencing (scRNA-seq), and to identify and validate the key genes BEX1 and MAP1b as potential therapeutic targets.

Methods: To comprehend the heterogeneity of SCLC and the tumor microenvironment, we used scRNA-seq to analyze the primary tumor and adjacent noncancerous tissue from a patient. The findings were tested with cell experiments.

Results: We observed that SCLC was mainly composed of neuroendocrine epithelial cells and displayed the immune-related cell failure state. The corresponding antitumor immune pathway activities were also downregulated, and the tumor microenvironment eventually showed immunosuppression. BEX1 and MAP1b were upregulated in most cell subtypes, which are verified by immunohistochemistry. In addition, downregulation of BEX1 in NCI-H209 and MAP1b in NCI-H82 significantly inhibited cell proliferation and migration, while increasing apoptosis. Based on preliminary data, BEX1 and MAP1b have been identified as promising candidates for the early diagnosis and therapy of SCLC; however, their clinical utility requires confirmation in subsequent studies. To investigate the heterogeneity and interaction among different cell types, we also constructed an intercellular communication network.

Conclusions: Our knowledge of the basic traits of SCLC is improved by this highly accurate single-cell study, which also offers fresh suggestions for potential future therapies.

Background: Circular RNAs (circRNAs) appear to exert critical functions in breast cancer (BC). The objective of this study is to explore the usefulness of circRNAs as potential diagnostic and prognostic biomarkers of BC.

Methods: The Gene Expression Omnibus (GEO) database was referenced to identify differentially expressed circRNAs in BC. Quantitative real-time polymerase chain reaction (qPCR) was used to detect the expression levels of hsa_circ_0001756 in both BC tissue samples and BC-derived cell lines. The functions of hsa_circ_0001756 were investigated both in vitro and in vivo. The luciferase reporter and rescue assays were used to clarify the molecular mechanisms of hsa_circ_0001756. Receiver operating characteristic (ROC) curve was established to evaluate the clinical value of hsa_circ_0001756 as a serum biomarker, and to investigate its potential correlation with the clinical pathological characteristics of BC patients by Chi-squared test.

Results: Hsa_circ_0001756 expression was upregulated in BC tissues and substantially correlated with tumor size and tumor-node-metastasis (TNM) stage. Knockdown (KD) of hsa_circ_0001756 markedly inhibited the malignant potential of BC both in vitro and in vivo. Mechanistically, hsa_circ_0001756 acted as a miR-584-5p sponge to regulate TRAF6 in BC cells. Serum levels of hsa_circ_0001756 were significantly higher in pre-operative BC patients than in healthy controls, fibroadenoma patients, and post-operative BC patients. Also, serum hsa_circ_0001756 was remarkably correlated with tumor size, patient age, metastasis state, and TNM stage. The combination of the traditional tumor markers carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) with hsa_circ_0001756 significantly improved the diagnostic accuracy of BC.

Conclusions: Our findings indicated that hsa_circ_0001756 could promote BC malignant progression through the miR-584-5p/TRAF6 signaling axis. Especially, hsa_circ_0001756 in serum holds promise as a biomarker for BC screening and diagnosis.

Background: Patients with acute leukemia are at increased risk of microbial infections due to factors such as the disease itself, intensive chemotherapy, and transplantation. Untimely or inadequate treatment can prolong therapy, raise costs, and even threaten patient survival, impacting overall cancer treatment outcomes. Traditional microbial identification relies on blood cultures (BCs), but their low positivity rate and lengthy processing time often hinder prompt diagnosis and the identification of the infecting pathogens. This study aimed to use droplet digital polymerase chain reaction (ddPCR), known for its sensitivity in single-molecule amplification, to detect pathogen DNA and drug-resistant genes in blood.

Methods: We included a total of 47 patients with hematologic malignancies who were over 18 years old and had neutropenia accompanied by fever [suspected bloodstream infection (BSI)] from August 2022 to November 2022. Patients who failed resuscitation after severe shock, with severe liver or kidney dysfunction, and in the terminal stage were excluded. We conducted ddPCR testing for bacteria/fungi/viruses with the patient's blood on the first day, third day, and fifth day of the occurrences of neutropenic fever with suspected BSI. In case of positive results indicating the presence of bacteria, we used the remaining nucleic acid samples to detect drug resistance genes.

Results: BC and ddPCR yielded positive results indicating the presence of bacteria in five patients (10.64%) and 14 patients (29.79%), respectively, with ddPCR demonstrating acceptable positive rate (81.44%). Regarding the breadth of detection, ddPCR identified 10 different pathogens, while only two pathogens went undetected. In contrast, BC detected only five different pathogens. In terms of the diversity of pathogens detected in single samples, among the 14 polymerase chain reaction (PCR)-positive patients, three had the presence of two different pathogens synchronously. Furthermore, ddPCR also revealed the presence of drug resistance genes. Among the 14 PCR-positive patients, four were found to have drug resistance genes, including one case of Klebsiella pneumoniae carbapenemase (rendering patients' immunocompromised system) and three cases of methicillin resistance determinant A (mecA).

Conclusions: ddPCR is a versatile and adaptable platform that can serve as a complement to traditional BCs.

Background: The signaling lymphocytic activation molecule family (SLAMF) members have recently been demonstrated to be potential targets in malignant tumors. The aim of this study is to explore the role of SLAMF member 9 (SLAMF9) in glioma.

Methods: Datasets from The Cancer Genome Atlas (TCGA) database were downloaded, and the correlation between SLAMF9 expression and the overall survival (OS) of glioma patients was analyzed. A tissue chip including 139 tumor tissues from glioma patients for immunohistochemistry (IHC) staining was used to detect the protein expression of SLAMF9, and the relationships between SLAMF9 expression and OS, disease-free survival (DFS), and clinicopathological features were analyzed. Multiplex immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry analysis, and bioinformatics analysis were used to detect the potential biological function of SLAMF9 in glioma.

Results: SLAMF9 expression was significantly higher in glioma tumor tissues than in normal tissues. High expression levels of SLAMF9 were correlated with shortened OS and DFS in glioma patients. Data from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) glioma dataset revealed that the protein expression of CD68 and CD163 was positively related to SLAMF9 expression in the tissues of glioma patients. In vivo, the levels of CD80 and CD86 were significantly increased, whereas the level of CD163 decreased after SLAMF9 knockdown in human macrophages. Functional analysis revealed that the pathways enriched in glioma tissues with high SLAMF9 expression were associated with immune response-related pathways.

Conclusions: This study is the first to highlight the important clinical value of SLAMF9 in patients with glioma.

Background: Hepatocellular carcinoma (HCC) ranks as a leading global cause of cancer-related mortality. Our study investigates the functional role between CD8⁺CD101⁺TIM3⁺ T cells (CCT) and CD8⁺CD101^-TIM3⁺ T cells in HCC, with a focus on their implications for immunotherapy.

Methods: We utilized single-cell RNA sequencing (scRNA-seq) to delineate the transcriptional landscapes and intercellular crosstalk of CCT and CD8⁺CD101^-TIM3⁺ T cells in HCC tissues. Clinical characteristics and scRNA-seq data were curated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. For the differentially expressed genes (DEGs), Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-enrichment were performed. Prognostic model was constructed using univariate Cox and least absolute shrinkage and selection operator (LASSO) Cox regression model, validated through Kaplan-Meier survival curves and receiver operating characteristic (ROC) curves. A corresponding nomogram was also established to predict the prognosis of HCC patients.

Results: Our results indicated that T cell re-clustering revealed four functionally distinct subsets: CD8⁺ T cells, CD8⁺CD101^-TIM3⁺ T cells, CCT, and CD4⁺ T cells. Pseudotime trajectory analysis demonstrated that CD8⁺CD101^-TIM3⁺ T cells progressively differentiated into CCT, a process mediated by MIF-CD74/CXCR4 and SPP1-CD44 signaling axes. Enrichment analysis identified 1,281 CCT-specific genes enriched in mitochondrial electron transport and oxidative phosphorylation pathways. The prognostic model showed strong discriminatory power for overall survival (OS), achieving areas under the curve of 0.825, 0.873, and 0.865 at 1, 3, and 5 years in the training cohort, compared to 0.654, 0.636, and 0.644 in the validation cohort. The developed nomogram effectively predicts OS for HCC patients.

Conclusions: Our findings elucidate the functional alterations of CCT and precursor cells within the context of HCC. The novel prognostic framework provides actionable insights for stratifying patients likely to benefit from combinatorial immunotherapy and chemotherapy.

Background and objective: Most sarcomas have complex karyotypes, making them particularly challenging to study and treat due to their genetic diversity and aggressive nature. Animal models are essential in sarcoma research as they provide a comprehensive approach to studying tumour biology, progression and therapeutic responses that cannot be fully replicated in vitro. However, choosing the right model requires consideration of many practical aspects that have not been adequately addressed, particularly in sarcomas. Therefore, we aim to fill this gap by focusing on several animal models used in sarcoma research.

Methods: We performed a literature search in Scopus, MEDLINE and Web of Science using specific search terms to identify published original in vivo studies regarding different sarcoma subtypes, as well as selection tools.

Key content and findings: The most commonly used models are: syngeneic, genetically engineered mouse (GEM), chemically induced, cell-derived xenografts (CDX), patient-derived xenografts (PDX), humanised PDX (huPDX), and zebrafish. Each model has its own advantages, for example: CDXs enable high-throughput drug screening, PDXs preserve tumour heterogeneity in patients, while huPDXs most closely resemble the human immune response, However, there are various limitations to each model, including a lack of genetic diversity in syngeneic models, the complexity and time requirements of GEMs, and the short life span of cost-effective zebrafish. We also described various tools that can be used to help select the right animal model, including the International Mouse Strain Resource (ISMR) and the Mouse Tumour Biology Database (MTB), and inoculation methods (e.g., subcutaneus, orthopic).

Conclusions: With the right model, researchers can accurately study tumour behaviour, therapeutic responses and the basic mechanisms that underlie sarcoma development. We provide a practical guide for animal model selection though detailed discussion of model classes, inoculation routes, and endpoint to sarcoma-specific use cases as well as a list of active repositories/databases.

Background: Phosphoglycerate dehydrogenase (PHGDH), the key rate-limiting enzyme responsible for controlling the serine biosynthetic pathway, has been implicated in metabolic reprogramming in numerous cancers. Despite this, its significance and regulatory mechanistic relevance in gastric cancer (GC) have yet to be fully elucidated. Here, we sought to elucidate the influence of PHGDH on autophagy and malignant phenotypes in GC and to elucidate its mechanistic relevance in GC progression.

Methods: GC tissues and adjacent noncancerous tissues (n=7 pairs) were assessed for PHGDH expression by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry. GC cell lines with differential PHGDH expression were screened, and stable knockdown and overexpression models were established. Functional assays, including MTS assays, colony formation, wound healing, and Transwell migration assays, were performed to evaluate proliferation and motility, respectively. Western blotting and autophagic flux assays, as well as analyses of live-cells expressing mRFP-GFP-LC3, were used to evaluate ROS production and autophagy.

Results: PHGDH was upregulated in GC tissues (n=7 pairs) with a stage-dependent trend, though larger cohorts are needed to confirm this pattern. Downregulation of PHGDH curtailed MGC803 cell growth, migratory and invasive abilities, and triggered apoptosis, while overexpression enhanced cell motility. Mechanistically, PHGDH silencing increased ROS and HIF-1α levels, reduced mTOR phosphorylation, and facilitated autophagic flux, as demonstrated by elevated LC3-II and reduced P62 expression. These changes were further confirmed by 3-MA/CQ treatment and mRFP-GFP-LC3 imaging. Notably, PHGDH downregulation may indirectly promote the assembly of the ULK1 complex through the concomitant upregulation of FIP200 and ATG101, thereby initiating autophagy.

Conclusions: These data suggest that PHGDH plays a role in the progression of GC and may be considered a potential therapeutic target upon further confirmation in larger clinical studies.