crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.

AIMS: With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear. METHODS: An in vivo shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents. RESULTS: VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model. CONCLUSION: This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.

Single-cell histone chaperones patterns guide intercellular communication of tumor microenvironment that contribute to breast cancer metastases.

BACKGROUND: Histone chaperones (HCs) are crucial for governing genome stability and gene expression in multiple cancers. However, the functioning of HCs in the tumor microenvironment (TME) is still not clearly understood. METHODS: Self-tested single-cell RNA-seq data derived from 6 breast cancer (BC) patients with brain and liver metastases were reanalyzed by nonnegative matrix factorization (NMF) algorithm for 36 HCs. TME subclusters were observed with BC and immunotherapy public cohorts to assess their prognosis and immune response. The biological effect of HSPA8, one of the HCs, was verified by transwell assay and wound-healing assays. RESULTS: Cells including fibroblasts, macrophages, B cells, and T cells, were classified into various subclusters based on marker genes. Additionally, it showed that HCs might be strongly associated with biological and clinical features of BC metastases, along with the pseudotime trajectory of each TME cell type. Besides, the results of bulk-seq analysis revealed that TME cell subclusters mediated by HCs distinguished significant prognostic value for BC patients and were relevant to patients' immunotherapy responses, especially for B cells and macrophages. In particular, CellChat analysis exhibited that HCs-related TME cell subclusters revealed extensive and diverse interactions with malignant cells. Finally, transwell and wound-healing assays exhibited that HSPA8 deficiency inhibited BC cell migration and invasion. CONCLUSIONS: Collectively, our study first dissected HCs-guided intercellular communication of TME that contribute to BC metastases.

Therapeutic Landscape of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Human epidermal growth factor receptor 2-positive breast cancer (HER2+BC) is a common malignancy that is prone to recurrence and metastasis in the early stages, resulting in a poor prognosis for patients. Many studies have suggested that targeted therapy promotes clinical outcomes in HER2+BC. With the introduction of trastuzumab in 1998, the prognosis of patients with early HER2+BC has improved significantly. However, owing to obstinate drug resistance and adverse events, the addition of new agents in standardized treatment has become a research hotspot. These promising agents include antibodies, antibody-drug conjugates, tyrosine kinase inhibitors, and anti-HER2 combined therapies. This article provides a brief description of the biology of BC and the expression of HER2, with the aim to provide an overview of the therapeutic landscape of HER2+BC by reviewing research results and introducing the latest evidence to provide a reference for clinical treatment.

Distribution of risk factors of ischemic stroke in Chinese young adults and its correlation with prognosis.

BACKGROUND: The risk factors for ischemic stroke in young people are complex, varied and closely related to prognosis. This study aims to analyze the risk factors for ischemic stroke in Chinese young people and to explore the main factors influencing the prognosis. METHOD: A total of 444 patients aged 16 to 45 years with ischemic stroke admitted to Suzhou tertiary hospital from 2011 to 2019 were retrospectively analyzed. Risk factors were identified according to the IPSS definition of pediatric stroke and the TOAST classification. All patients were followed up, and the modified Rankin score was used to evaluate the prognosis. Logistic regression analysis was used to explore the influencing factors of poor prognosis. RESULTS: Among the patients, 12 risk factors were found according to the IPSS definition of pediatric stroke, and 5 types of stroke were found according to the TOAST classification. A total of 299 patients had a good prognosis. Anemia, venous sinus thrombosis, isolated large-vessel occlusion, and high baseline NIHSS score were significant risk factors. CONCLUSION: The IPSS definition enables patients to be classified on the basis of more risk factors than other classification methods. The prognosis of ischemic stroke in young people is generally good in the 5 years following the event. Anemia, venous sinus thrombosis, isolated large-vessel occlusion and high baseline NIHSS score were associated with poor prognosis.

The Pan-Cancer Multi-Omics Landscape of FOXO Family Relevant to Clinical Outcome and Drug Resistance.

The forkhead box O (FOXO) transcription factors (TFs) family are frequently mutated, deleted, or amplified in various human cancers, making them attractive candidates for therapy. However, their roles in pan-cancer remain unclear. Here, we evaluated the expression, prognostic value, mutation, methylation, and clinical features of four FOXO family genes (FOXO1, FOXO3, FOXO4, and FOXO6) in 33 types of cancers based on the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. We used a single sample gene set enrichment analysis (ssGSEA) algorithm to establish a novel index called "FOXOs score". Moreover, we investigated the association between the FOXOs score and tumor microenvironment (TME), the responses to multiple treatments, along with drug resistance. We found that the FOXO family genes participated in tumor progression and were related to the prognosis in various types of cancer. We calculated the FOXOs score and found that it was significantly correlated with multiple malignant pathways in pan-cancer, including Wnt/beta-catenin signaling, TGF-beta signaling, and hedgehog signaling. In addition, the FOXOs score was also associated with multiple immune-related characteristics. Furthermore, the FOXOs score was sensitive for predicting the efficacy of diverse treatments in multiple cancers, especially immunotherapy. In conclusion, FOXO family genes were vital in pan-cancer and were strongly correlated with the TME. A high FOXOs score indicated an excellent immune-activated TME and sensitivity to multiple treatments. Hence, the FOXOs score might potentially be used as a biomarker in patients with a tumor.

Predictive Nomogram of Subsequent Liver Metastasis After Mastectomy or Breast-Conserving Surgery in Patients With Nonmetastatic Breast Cancer.

BACKGROUND: Metastasis accounts for the majority of deaths in patients with breast cancer. Liver metastasis is reported common for breast cancer patients. The purpose of this study was to construct a nomogram to predict the likelihood of subsequent liver metastasis in patients with nonmetastatic breast cancer, thus high-risk patient populations can be prevented and monitored. METHODS: A total of 1840 patients with stage I-III breast cancer were retrospectively included and analyzed. A nomogram was constructed to predict liver metastasis based on multivariate logistic regression analysis. SEER database was used for external validation. C-index, calibration curve and decision curve analysis were used to evaluate the predictive performance of the model. RESULTS: The nomogram included 3 variables related to liver metastasis: HER2 status (odds ratio (OR) 1.86, 95%CI 1.02 to 3.41; P = 0.045), tumor size (OR 3.62, 1.91 to 6.87; P < 0.001) and lymph node metastasis (OR 2.26, 1.18 to 4.34; P = 0.014). The C index of the training cohort, internal validation cohort and external validation cohort were 0.699, 0.814 and 0.791, respectively. The nomogram was well-calibrated, with no statistical difference between the predicted and the observed probabilities. CONCLUSION: We have developed and validated a robust tool enabled to predict subsequent liver metastasis in patients with nonmetastatic breast cancer. Distinguishing a population of patients at high risk of liver metastasis will facilitate preventive treatment or monitoring of liver metastasis.

Diagnostic and prognostic value of circular RNA CDR1as/ciRS-7 for solid tumours: A systematic review and meta-analysis.

The circular RNA, CDR1as/ciRS-7, functions as a vital regulator in various cancers; however, the predictive value of CDR1as remains controversial. Therefore, a comprehensive analysis for clarifying the precise diagnostic and prognostic value of CDR1as in solid tumours is needed. A literature review of several databases was conducted for identifying potential studies. Pooled odds ratios (ORs) and hazard ratios (HRs) were used for evaluating the diagnostic accuracy variables and survival. Overall, 15 studies (1787 patients) and 11 studies (1578 patients) were included for diagnostic and prognostic outcome syntheses, respectively. Up-regulated CDR1as expression was found to be correlated with worse clinicopathological characteristics, including the T status, N status, histological grade, TNM stage and distant metastasis. The synthesized sensitivity was 0.72 (95% confidence interval [CI], 0.65-0.79), and the specificity was 0.80 (95% CI, 0.74-0.86). The positive likelihood ratio (LR), negative LR and diagnostic odds ratio (DOR) were 3.70, 0.34 and 10.80, respectively. The area under the receiver operator characteristic curve was 0.84 (95% CI, 0.80-0.87). In the pooled prognostic analysis, patients with high CDR1as expression had worse overall survival (HR = 2.40, P < 0.001) and disease-free survival (HR = 1.74, P < 0.001). These results suggest that CDR1as is a reliable diagnostic and prognostic biomarker with high accuracy and efficiency, which may potentially facilitate clinical decisions on solid tumours in the future.

Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple-negative breast cancer.

Our study aims to construct a prognosis-related immune phenotype classifier for predicting clinical prognosis and immune activity in triple-negative breast cancer (TNBC). A total of 237 patients with TNBC from Sun Yat-sen University Cancer Center (SYSUCC) and 533 patients with TNBC from public datasets were included in our study. A stromal immune quantified index was generated with a LASSO Cox regression model based on five prognosis-related immune cells evaluated by CIBERSORT or IHC and was used to determine immune phenotypes. Immune features were evaluated in the samples before chemotherapy. A total of 119 patients in the SYSUCC training cohort were classified into immune Phenotypes A and B according to the density of stromal CD4+ T cells, γδ T cells, monocytes, M1 macrophages and M2 macrophages. Phenotype A predicted better survival than Phenotype B, and the classification was further validated in the testing cohort of 118 patients and the validation cohort of 533 patients. In the combined cohort, significant differences were found in Phenotype A compared to Phenotype B for the 5-year overall survival (83.5% vs 65.8%, respectively, P < .01) and the 5-year disease-free survival (87.3% vs 76.0%, respectively, P < .01). In Phenotype A, immune-related pathways were significantly enriched, and a higher level of immune checkpoint molecules, including PD-L1, PD-1 and CTLA-4, could be observed. The immune phenotype classification was an independent prognostic indicator for TNBC and might serve as a potential predictor for immune activity within the tumor microenvironment.

Breast-Conserving Therapy Versus Mastectomy in Young Breast Cancer Patients Concerning Molecular Subtypes: A SEER Population-Based Study.

Breast-conserving therapy was once a contraindication in young breast cancer patients (aged ≤40 years). Emerging studies suggest that breast-conserving therapy and mastectomy could achieve similar prognosis in this population. However, the effect of molecular subtype disparity on surgical strategy in these patients remains unclear. Data from 8656 young patients (aged ≤40 years) diagnosed with invasive breast cancer between in 2010 and 2014 were retrospectively reviewed from the Surveillance, Epidemiology, and End Results database. The Cox proportional hazards model was used to evaluate subtype-dependent relationships between the surgical method and survival. Of the 8656 patients, 4132 (47.7%) underwent breast-conserving therapy and 4524 (52.3%) underwent mastectomy. The median follow-up period was 30.0 months. Patients in the breast-conserving therapy group demonstrated better overall survival and breast cancer-specific survival than those in the mastectomy group (both p < 0.05). Patients with different molecular subtypes exhibited significant differences in overall survival and breast cancer-specific survival (p < 0.001). Patients with luminal subtypes experienced better overall survival and breast cancer-specific survival than those with the triple-negative subtype. Multivariate analysis revealed that overall mortality risk of the breast-conserving therapy group was lower than that of the mastectomy group among HR(+)HER-2(-) and HR(-)HER-2(-) patients (overall mortality risk of 36.3% [adjusted hazard ratio = 0.637 {95% confidence interval = 0.448-0.905}, p = 0.012] and 36.0% [adjusted hazard ratio = 0.640 {95% confidence interval = 0.455-0.901}, p = 0.010] respectively.) The breast cancer-specific mortality risk was also lower by a percentage similar to that of the overall mortality risk. In the HR(+)HER-2(+) group, the surgical method was an independent prognostic factor for breast cancer-specific survival (adjusted hazard ratio = 0.275 [95% confidence interval = 0.089-0.849], p = 0.025), while there was a trend that patients with breast-conserving therapy had better overall survival than those with mastectomy (p = 0.056). In the HR(-)HER-2(+) group, no significant difference was observed in overall survival and breast cancer-specific survival (p = 0.791 and p = 0.262, respectively). Breast-conserving therapy resulted in significantly better prognosis in patients with luminal and triple-negative subtypes, while no significant difference was observed in patients with the HER-2 enriched subtype. These results may be helpful in informing clinically precise decision-making for surgery in this population.

[Gly14]-humanin restores cathepsin D function via FPRL1 and promotes autophagic degradation of Ox-LDL in HUVECs.

BACKGROUND AND AIM: Abnormal aggregation of oxidized low-density lipoprotein (Ox-LDL) in vascular endothelial cells (VECs) is one of the major pathological changes in atherosclerotic lesions. Our research aimed to assess the mechanism of humanin (HN) in promoting autophagic degradation of Ox-LDL in HUVECs. METHODS AND RESULTS: Flow cytometry and lipid quantitation results showed that Ox-LDL caused lipid and cholesterol accumulation in HUVECs. Western blot results showed that Ox-LDL increased the expression of autophagy-related proteins P62 and LC3-II in a concentration-dependent manner. The cathepsin D activity assay showed that Ox-LDL inhibited the function of cathepsin D. HNG pretreatment reduced lipid and cholesterol aggregation in HUVECs induced by Ox-LDL, increased LC3-II protein level, decreased P62 protein content, and reversed Ox-LDL-induced cathepsin D functional impairment. Inhibition of the FPRL1 pathway by FPRL1 siRNA or the FPRL1-specific inhibitor Boc-MLF blocked all HNG's protective effects. These results indicate that HNG could restore cathepsin D activity and protein level in HUVECs to repair lysosomal functional damage induced by Ox-LDL, further repairing Ox-LDL-induced autophagic damage in HUVECs. CONCLUSION: HNG restores the activity of Ox-LDL-induced damaged lysosomal enzyme cathepsin D through its membrane protein receptor FPRL1 to promote autophagic degradation of Ox-LDL in HUVECs.

circRAD18 sponges miR-208a/3164 to promote triple-negative breast cancer progression through regulating IGF1 and FGF2 expression.

As a new rising star of non-coding RNA, circular RNAs (circRNAs) emerged as vital regulators with biological functions in diverse of cancers. However, the function and precise mechanism of the vast majority of circRNAs in triple-negative breast cancer (TNBC) occurrence and progression have not been clearly elucidated. In the current study, we identified and further investigated hsa_circ_0002453 (circRAD18) by analyzing our previous microarray profiling. Expression of circRAD18 was found significantly upregulated in TNBC compared with normal mammary tissues and cell lines. circRAD18 was positively correlated with T stage, clinical stage and pathological grade and was an independent risk factor for TNBC patients. We performed proliferation, colony formation, cell migration, apoptosis and mouse xenograft assays to verify the functions of circRAD18. Knockdown of circRAD18 significantly suppressed cell proliferation and migration, promoted cell apoptosis and inhibited tumor growth in functional and xenograft experiments. Through luciferase reporter assays, we confirmed that circRAD18 acts as a sponge of miR-208a and miR-3164 and promotes TNBC progression through upregulating IGF1 and FGF2 expression. Altogether, our research revealed the pivotal role of circRAD18-miR-208a/3164-IGF1/FGF2 axis in TNBC tumorigenesis and metastasis though the mechanism of competing endogenous RNAs. Thus, circRAD18 may serve as a novel prognostic biomarker and potential target for TNBC treatment in the future.

Identification of a 4-mRNA metastasis-related prognostic signature for patients with breast cancer.

Metastasis-related mRNAs have showed great promise as prognostic biomarkers in various types of cancers. Therefore, we attempted to develop a metastasis-associated gene signature to enhance prognostic prediction of breast cancer (BC) based on gene expression profiling. We firstly screened and identified 56 differentially expressed mRNAs by analysing BC tumour tissues with and without metastasis in the discovery cohort (GSE102484, n = 683). We then found 26 of these differentially expressed genes were associated with metastasis-free survival (MFS) in the training set (GSE20685, n = 319). A metastasis-associated gene signature built using a LASSO Cox regression model, which consisted of four mRNAs, can classify patients into high- and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter MFS (hazard ratio [HR] 3.89, 95% CI 2.53-5.98; P < 0.001), disease-free survival (DFS) (HR 4.69, 2.93-7.50; P < 0.001) and overall survival (HR 4.06, 2.56-6.45; P < 0.001) than patients with low-risk scores. The prognostic accuracy of mRNAs signature was validated in the two independent validation cohorts (GSE21653, n = 248; GSE31448, n = 246). We then developed a nomogram based on the mRNAs signature and clinical-related risk factors (T stage and N stage) that predicted an individual's risk of disease, which can be assessed by calibration curves. Our study demonstrated that this 4-mRNA signature might be a reliable and useful prognostic tool for DFS evaluation and will facilitate tailored therapy for BC patients at different risk of disease.

The PROTAC technology in drug development.

Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. SIGNIFICANCE OF THE STUDY: This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

Evolutionary Trend Analysis of Research on Immunotherapy for Brain Metastasis Based on Machine-Learning Scientometrics.

Brain metastases challenge cancer treatments with poor prognoses, despite ongoing advancements. Immunotherapy effectively alleviates advanced cancer, exhibiting immense potential to revolutionize brain metastasis management. To identify research priorities that optimize immunotherapies for brain metastases, 2164 related publications were analyzed. Scientometric visualization via R software, VOSviewer, and CiteSpace showed the interrelationships among literature, institutions, authors, and topic areas of focus. The publication rate and citations have grown exponentially over the past decade, with the US, China, and Germany as the major contributors. The University of Texas MD Anderson Cancer Center ranked highest in publications, while Memorial Sloan Kettering Cancer Center was most cited. Clusters of keywords revealed six hotspots: 'Immunology', 'Check Point Inhibitors', 'Lung Cancer', 'Immunotherapy', 'Melanoma', 'Breast Cancer', and 'Microenvironment'. Melanoma, the most studied primary tumor with brain metastases offers promising immunotherapy advancements with generalizability and adaptability to other cancers. Our results outline the holistic overview of immunotherapy research for brain metastases, which pinpoints the forefront in the field, and directs researchers toward critical inquiries for enhanced mechanistic insight and improved clinical outcomes. Moreover, governmental and funding agencies will benefit from assigning financial resources to entities and regions with the greatest potential for combating brain metastases through immunotherapy.

Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies.

Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.

Multi-omics analysis of disulfidptosis regulators and therapeutic potential reveals glycogen synthase 1 as a disulfidptosis triggering target for triple-negative breast cancer.

Disruption of disulfide homeostasis during biological processes can have fatal consequences. Excess disulfides induce cell death in a novel manner, termed as "disulfidptosis." However, the specific mechanism of disulfidptosis has not yet been elucidated. To determine the cancer types sensitive to disulfidptosis and outline the corresponding treatment strategies, we firstly investigated the crucial functions of disulfidptosis regulators pan-cancer at multi-omics levels. We found that different tumor types expressed dysregulated levels of disulfidptosis regulators, most of which had an impact on tumor prognosis. Moreover, we calculated the disulfidptosis activity score in tumors and validated it using multiple independent datasets. Additionally, we found that disulfidptosis activity was correlated with classic biological processes and pathways in various cancers. Disulfidptosis activity was also associated with tumor immune characteristics and could predict immunotherapy outcomes. Notably, the disulfidptosis regulator, glycogen synthase 1 (GYS1), was identified as a promising target for triple-negative breast cancer and validated via in vitro and in vivo experiments. In conclusion, our study elucidated the complex molecular phenotypes and clinicopathological correlations of disulfidptosis regulators in tumors, laying a solid foundation for the development of disulfidptosis-targeting strategies for cancer treatment.

Single-cell RNA sequencing elucidated the landscape of breast cancer brain metastases and identified ILF2 as a potential therapeutic target.

Distant metastasis remains the primary cause of morbidity in patients with breast cancer. Hence, the development of more efficacious strategies and the exploration of potential targets for patients with metastatic breast cancer are urgently needed. The data of six patients with breast cancer brain metastases (BCBrM) from two centres were collected, and a comprehensive landscape of the entire tumour ecosystem was generated through the utilisation of single-cell RNA sequencing. We utilised the Monocle2 and CellChat algorithms to investigate the interrelationships among each subcluster. In addition, multiple signatures were collected to evaluate key components of the subclusters through multi-omics methodologies. Finally, we elucidated common expression programs of malignant cells, and experiments were conducted in vitro and in vivo to determine the functions of interleukin enhancer-binding factor 2 (ILF2), which is a key gene in the metastasis module, in BCBrM progression. We found that subclusters in each major cell type exhibited diverse characteristics. Besides, our study indicated that ILF2 was specifically associated with BCBrM, and experimental validations further demonstrated that ILF2 deficiency hindered BCBrM progression. Our study offers novel perspectives on the heterogeneity of BCBrM and suggests that ILF2 could serve as a promising biomarker or therapeutic target for BCBrM.

The burgeoning importance of PIWI-interacting RNAs in cancer progression.

PIWI-interacting RNAs (piRNAs) are a class of small noncoding RNA molecules that specifically bind to piwi protein family members to exert regulatory functions in germ cells. Recent studies have found that piRNAs, as tissue-specific molecules, both play oncogenic and tumor suppressive roles in cancer progression, including cancer cell proliferation, metastasis, chemoresistance and stemness. Additionally, the atypical manifestation of piRNAs and PIWI proteins in various malignancies presents a promising strategy for the identification of novel biomarkers and therapeutic targets in the diagnosis and management of tumors. Nonetheless, the precise functions of piRNAs in cancer progression and their underlying mechanisms have yet to be fully comprehended. This review aims to examine current research on the biogenesis and functions of piRNA and its burgeoning importance in cancer progression, thereby offering novel perspectives on the potential utilization of piRNAs and piwi proteins in the management and treatment of advanced cancer.

Pan-Cancer Single-Cell and Spatial-Resolved Profiling Reveals the Immunosuppressive Role of APOE+ Macrophages in Immune Checkpoint Inhibitor Therapy.

The heterogeneity of macrophages influences the response to immune checkpoint inhibitor (ICI) therapy. However, few studies explore the impact of APOE+ macrophages on ICI therapy using single-cell RNA sequencing (scRNA-seq) and machine learning methods. The scRNA-seq and bulk RNA-seq data are Integrated to construct an M.Sig model for predicting ICI response based on the distinct molecular signatures of macrophage and machine learning algorithms. Comprehensive single-cell analysis as well as in vivo and in vitro experiments are applied to explore the potential mechanisms of the APOE+ macrophage in affecting ICI response. The M.Sig model shows clear advantages in predicting the efficacy and prognosis of ICI therapy in pan-cancer patients. The proportion of APOE+ macrophages is higher in ICI non-responders of triple-negative breast cancer compared with responders, and the interaction and longer distance between APOE+ macrophages and CD8+ exhausted T (Tex) cells affecting ICI response is confirmed by multiplex immunohistochemistry. In a 4T1 tumor-bearing mice model, the APOE inhibitor combined with ICI treatment shows the best efficacy. The M.Sig model using real-world immunotherapy data accurately predicts the ICI response of pan-cancer, which may be associated with the interaction between APOE+ macrophages and CD8+ Tex cells.

Autophagy Deficiency Induced by SAT1 Potentiates Tumor Progression in Triple-Negative Breast Cancer.

Aggressive triple-negative breast cancer (TNBC) still lacks approved targeted therapies, requiring more exploration of its underlying mechanisms. Previous studies have suggested a potential role of SAT1 (Spermidine/Spermine N1-acetyltransferase 1) in cancer, which needs to be further elucidated in breast cancer. In this study, highly expressed SAT1 in TNBC signified worse patient prognoses. And SAT1 knockdown effectively inhibited the proliferation and migration abilities of TNBC cells in vitro and in vivo. In terms of mechanism, the transcription factor JUN enhanced SAT1 transcriptional activity by binding to its promoter region. Then, SAT1 protein in the cytoplasm engaged in directly binding with YBX1 for sustaining YBX1 protein stability via deubiquitylation mediated by the E3 ligase HERC5. Further, SAT1 was found to suppress autophagy remarkably via stabilization of mTOR mRNA with the accumulation of YBX1-mediated methyl-5-cytosine (m5C) modification. These findings proved that SAT1 drives TNBC progression through the SAT1/YBX1/mTOR axis, which may provide a potential candidate for targeted therapy in advanced TNBC.