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The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.
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Resistance to trastuzumab and the poor efficacy of subsequent chemotherapy have become major challenges for HER2-positive gastric cancer (GC). As resistance evolves, tumor cells may acquire a new drug susceptibility profile, profoundly impacting the subsequent treatment selection and patient survival. However, the interplay between trastuzumab and other types of drugs in HER2-positive GC remains elusive. In our study, we utilized resistant cell lines and tissue specimens to map the drug susceptibility profile of trastuzumab-resistant GC, discovering that resistance to trastuzumab induces collateral resistance to commonly used chemotherapeutic agents. Additionally, patients with collateral resistance distinguished by a 13-gene scoring model in HER2-positive GC cohorts are predicted to have a poor prognosis and may be sensitive to cholesterol-lowering drugs. Mechanistically, endosomal cholesterol transport is further confirmed to enrich cholesterol in the plasma membrane, contributing to collateral resistance through the Hedgehog-ABCB1 axis. As a driver for cholesterol, Cdc42 is activated by the formation of the NPC1-TßRI-Cdc42 complex to facilitate endosomal cholesterol transport. We demonstrated that inhibiting Cdc42 activation with ZCL278 reduces cholesterol levels in the plasma membrane and reverses collateral resistance between trastuzumab and chemotherapy in vitro and in vivo. Collectively, our findings verify the phenomena and mechanism of collateral resistance between trastuzumab and chemotherapy, and propose a potential therapeutic target and strategy in the second-line treatment for trastuzumab-resistant HER2-positive GC.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Trastuzumab/farmacología , Resistencia a Antineoplásicos , Línea Celular TumoralRESUMEN
ALG3 has significant modulatory function in the process of tumor development. Yet how ALG3 involves in the advancement of different malignancies isn't fully understood. We performed a pan-cancer assessment on ALG3 utilizing datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to examine its tumor-related roles across malignancies and its link to particular molecules and cells in the tumor microenvironment (TME). Furthermore, we focused on breast cancer to examine the influence of ALG3-mediated signaling pathways and intercellular interactions in the advancement of tumors. The biological effects of ALG3 were verified by breast cancer cells. Enhanced ALG3 expression was discovered to be substantially linked to patients' grim prognoses in a number of malignancies. Furthermore, the expression of ALG3 in the TME was linked to the infiltration of stromal and immune cells, and ALG3-related immune checkpoints, TMB, and MSI were also discovered. We also discovered that cancer patients having a high level of ALG3 exhibited a lower probability of benefiting from immunotherapy. Furthermore, our research found that KEGG enrichment, single-cell RNA and spatial sequencing analyses were effective in identifying key signaling pathways in ALG3-associated tumor growth. In vitro, knockdown of ALG3 could decrease the proliferation of breast cancer cells. In summary, our research offers a comprehensive insight into the advancement of tumors under the mediation of ALG3. ALG3 appears to be intimately associated with tumor development in the TME. ALG3 might be a viable treatment target for cancer therapy, particularly in the case of breast cancer.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Biomarcadores , Inmunoterapia , ARN , Análisis Espacial , Pronóstico , Microambiente Tumoral/genética , ManosiltransferasasRESUMEN
In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation.
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Autofagia , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteolisis , Proteínas Mutantes/metabolismo , Proteínas Mutantes/farmacología , Línea Celular Tumoral , Péptidos/metabolismo , Lípidos/farmacologíaRESUMEN
Ferroptosis is a type of regulated cell death characterized by iron accumulation and lipid peroxidation. The molecular mechanisms underlying ferroptosis regulation in non-small cell lung cancer (NSCLC) are poorly understood. In this study, we found that protein kinase A (PKA) inhibition enhanced ferroptosis susceptibility in NSCLC cells, as evidenced by reduced cell viability and increased lipid peroxidation. We further identified cAMP-responsive element protein 1 (CREB1), a transcription factor and a substrate of PKA, as a key regulator of ferroptosis. Knockdown of CREB1 sensitized NSCLC cells to ferroptosis inducers (FINs) and abolished the effects of PKA inhibitor and agonist, revealing the pivotal role of CREB1 in ferroptosis regulation. Using a high-throughput screening approach and subsequent validation by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, we discovered that CREB1 transcriptionally activated stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids. SCD conferred ferroptosis resistance by decreasing the availability of polyunsaturated fatty acids for lipid peroxidation, and its overexpression rescued the effect of CREB1 knockdown on ferroptosis in vitro. Besides, CREB1 knockdown suppressed xenograft tumor growth in the presence of Imidazole Ketone Erastin (IKE), a potent FIN, and this effect was reversed by SCD. Finally, we showed that high expression of CREB1 was associated with poor prognosis in NSCLC patients from public datasets and our institution. Collectively, this study illustrates the effect of PKA/CREB1/SCD axis in regulating ferroptosis of NSCLC, targeting this pathway may provide new strategies for treating NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Ferroptosis , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Ferroptosis/genética , Peroxidación de Lípido , Neoplasias Pulmonares/genéticaRESUMEN
Chronic stress is a known risk factor for breast cancer, yet the underlying mechanisms are unclear. This study explores the potential involvement of microbial and metabolic signals in chronic stress-promoted breast cancer progression, revealing that reduced abundances of Blautia and its metabolite acetate may contribute to this process. Treatment with Blautia and acetate increases antitumor responses of CD8+ T cells and reverses stress-promoted breast cancer progression in female mice. Patients with depression exhibit lower abundances of Blautia and acetate, and breast cancer female patients with depression display lower abundances of acetate, decreased numbers of tumor-infiltrating CD8+ T cells, and an increased risk of metastasis. These results suggest that Blautia-derived acetate plays a crucial role in modulating the immune response to breast cancer, and its reduction may contribute to chronic stress-promoted cancer progression. Our findings advance the understanding of microbial and metabolic signals implicated in cancer in patients with depression and may provide therapeutic options for female patients with breast cancer and depression.
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Neoplasias de la Mama , Femenino , Humanos , Ratones , Animales , Neoplasias de la Mama/metabolismo , Linfocitos T CD8-positivosRESUMEN
Background: N6-methyladenosine (m6A) RNA methylation plays a crucial role in important genomic processes in a variety of malignancies. However, the characterization of m6A with infiltrating immune cells in the tumor microenvironment (TME) in esophageal squamous carcinoma (ESCC) remains unknown. Methods: The single-cell transcriptome data from five ESCC patients in our hospital were analyzed, and TME clusters associated with prognosis and immune checkpoint genes were investigated. Cell isolation and qPCR were conducted to validate the gene characterization in different cells. Results: According to distinct biological processes and marker genes, macrophages, T cells, and B cells clustered into three to four different subgroups. In addition, we demonstrated that m6A RNA methylation regulators were strongly related to the clinical and biological features of ESCC. Analysis of transcriptome data revealed that m6A-mediated TME cell subsets had high predictive value and showed a close relationship with immune checkpoint genes. The validation results from qPCR demonstrated the characteristics of essential genes. CellChat analysis revealed that RNA from TME cells m6A methylation-associated cell subtypes had substantial and diversified interactions with cancer cells. Further investigation revealed that MIF- (CD74+CXCR4) and MIF- (CD74+CD44) ligand-receptor pairings facilitated communication between m6A-associated subtypes of TME cells and cancer cells. Conclusion: Overall, our study demonstrated for the first time the function of m6A methylation-mediated intercellular communication in the microenvironment of tumors in controlling tumor development and anti-tumor immune regulation in ESCC.
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BACKGROUND: Sauchinone is extracted from the root of Saururus chinensis and exhibits potent antitumor effects in various human cancers. However, how sauchinone is involved in breast cancer has not been well studied. METHODS: Cells apoptosis, cell proliferation, and cycle distribution were evaluated. Xenograft tumor mouse model was constructed to investigate the roles of sauchinone. The relevant protein expression was detected by western blot. RESULTS: We found that sauchinone significantly reduced proliferation and survival, also induced apoptosis of MCF-7 and Bcap-37 cells in vitro. Sauchinone significantly increased miR-148a-3p expression, and human epidermal growth factor receptor (HER)-2 targeted on miR-148a-3p. Sauchinone exposure downregulated HER-2 expression whose overexpression partly eliminated the inhibitory effect of sauchinone. Further, sauchinone efficiently inhibited breast cancer progression through downregulating HER-2 expression in vivo. CONCLUSION: Our results indicate that sauchinone efficiently inhibits breast cancer progression through regulating miR-148a-3p/HER-2 axis, suggesting that sauchinone could be an effective anticancer agent for breast cancer.
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Neoplasias de la Mama , MicroARNs , Animales , Femenino , Humanos , Ratones , Benzopiranos/farmacología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismoRESUMEN
Recently, semantic segmentation has been widely applied in various realistic scenarios. Many semantic segmentation backbone networks use various forms of dense connection to improve the efficiency of gradient propagation in the network. They achieve excellent segmentation accuracy but lack inference speed. Therefore, we propose a backbone network SCDNet with a dual path structure and higher speed and accuracy. Firstly, we propose a split connection structure, which is a streamlined lightweight backbone with a parallel structure to increase inference speed. Secondly, we introduce a flexible dilated convolution using different dilation rates so that the network can have richer receptive fields to perceive objects. Then, we propose a three-level hierarchical module to effectively balance the feature maps with multiple resolutions. Finally, a refined flexible and lightweight decoder is utilized. Our work achieves a trade-off of accuracy and speed on the Cityscapes and Camvid datasets. Specifically, we obtain a 36% improvement in FPS and a 0.7% improvement in mIoU on the Cityscapes test set.
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Tamoxifen is the most commonly used treatment for estrogen-receptor (ER) positive breast cancer patients, but its efficacy is severely hampered by resistance. PI3K/AKT/mTOR pathway inhibition was proven to augment the benefit of endocrine therapy and exhibited potential for reversing tamoxifen-induced resistance. However, the vast majority of PI3K inhibitors currently approved for clinical use are unsatisfactory in terms of safety and efficacy. We developed two-dimensional CuPd (2D-CuPd) nanosheets with oxidase and peroxidase nanozyme activities to offer a novel solution to inhibit the activity of the PI3K/AKT/mTOR pathway. 2D-CuPd exhibit superior dual nanozyme activities converting hydrogen peroxide accumulated in drug-resistant cells into more lethal hydroxyl radicals while compensating for the insufficient superoxide anion produced by tamoxifen. The potential clinical utility was further demonstrated in an orthotopically implanted tamoxifen-resistant PDX breast cancer model. Our results reveal a novel nanozyme ROS-mediated protein mechanism for the regulation of the PI3K subunit, illustrate the cellular pathways through which increased p85ß protein expression contributes to tamoxifen resistance, and reveal p85ß protein as a potential therapeutic target for overcoming tamoxifen resistance. 2D-CuPd is the first reported nanomaterial capable of degrading PI3K subunits, and its high performance combined with further materials engineering may lead to the development of nanozyme-based tumor catalytic therapy.
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Neoplasias de la Mama , Tamoxifeno , Femenino , Humanos , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Cobre , Plomo , NanoestructurasRESUMEN
The tumor microenvironment (TME) is a very cunning system that enables tumor cells to escape death post-traditional antitumor treatments through the comprehensive effect of different factors, thereby leading to drug resistance. Deep insights into TME characteristics and tumor resistance encourage the construction of nanomedicines that can remodel the TME against drug resistance. Tremendous interest in combining TME-regulation measurement with traditional tumor treatment to fight multidrug-resistant tumors has been inspired by the increasing understanding of the role of TME reconstruction in improving the antitumor efficiency of drug-resistant tumor therapy. This review focuses on the underlying relationships between specific TME characteristics (such as hypoxia, acidity, immunity, microorganisms, and metabolism) and drug resistance in tumor treatments. The exciting antitumor activities strengthened by TME regulation are also discussed in-depth, providing solutions from the perspective of nanomedicine design. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
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Nanomedicina , Neoplasias , Humanos , Microambiente Tumoral , Neoplasias/terapia , Sistemas de Liberación de MedicamentosRESUMEN
Background: Breast carcinoma is well recognized to be having the highest global occurrence rate among all cancers, being the leading cause of cancer mortality in females. The aim of this study was to elucidate breast cancer at the genomic and transcriptomic levels in different subtypes so that we can develop more personalized treatments and precision medicine to obtain better outcomes. Method: In this study, an expression profiling dataset downloaded from the Gene Expression Omnibus database, GSE45827, was re-analyzed to compare the expression profiles of breast cancer samples in the different subtypes. Using the GEO2R tool, different expression genes were identified. Using the STRING online tool, the protein-protein interaction networks were conducted. Using the Cytoscape software, we found modules, seed genes, and hub genes and performed pathway enrichment analysis. The Kaplan-Meier plotter was used to analyze the overall survival. MicroRNAs and transcription factors targeted different expression genes and were predicted by the Enrichr web server. Result: The analysis of these elements implied that the carcinogenesis and development of triple-negative breast cancer were the most important and complicated in breast carcinoma, occupying the most different expression genes, modules, seed genes, hub genes, and the most complex protein-protein interaction network and signal pathway. In addition, the luminal A subtype might occur in a completely different way from the other three subtypes as the pathways enriched in the luminal A subtype did not overlap with the others. We identified 16 hub genes that were related to good prognosis in triple-negative breast cancer. Moreover, SRSF1 was negatively correlated with overall survival in the Her2 subtype, while in the luminal A subtype, it showed the opposite relationship. Also, in the luminal B subtype, CCNB1 and KIF23 were associated with poor prognosis. Furthermore, new transcription factors and microRNAs were introduced to breast cancer which would shed light upon breast cancer in a new way and provide a novel therapeutic strategy. Conclusion: We preliminarily delved into the potentially comprehensive molecular mechanisms of breast cancer by creating a holistic view at the genomic and transcriptomic levels in different subtypes using computational tools. We also introduced new prognosis-related genes and novel therapeutic strategies and cast new light upon breast cancer.
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Very few studies have been done in HER2 positive patients without complete pathological response (pCR) after combined neoadjuvant chemo- and HER2-target therapy to investigate changes in intrinsic subtype, risk of recurrence (ROR) score, and immunity status before and after treatment. Patients with nonmetastatic HER2-positive breast cancer failed to achieve pCR after neoadjuvant chemotherapy plus trastuzumab were included in current study. We examined the distribution of PAM50 subtypes, ROR score and immunity score in 25 paired baseline and surgical samples. The Miller-Payne grading system was used to evaluate the efficacy of the neoadjuvant therapy. It was observed that the distribution of intrinsic subtype, ROR category and immunity subgroup varied according to hormone receptor (HR) status. HER2-enriched and basal-like subtypes, median-high ROR categories and immunity-weak subgroup were dominant in baseline tumors. Compared to baseline samples, conversion of intrinsic subtype, ROR categories and immunity subgroups were found in 15 (60.0%), 13(52.0%), and 11(44.0%) surgical samples, respectively. The PAM50 subtype, ROR category, and immunity subgroup were concordant between baseline and surgical samples where nonluminal subtypes, median-high ROR categories and i-weak subgroup were still common. In conclusion, the HER2-positive breast cancer is highly heterogeneous with a distribution of 72-gene expression varying according to HR co-expression. The dynamics of the 72-gene expression pre- and posttreatment may become novel biomarker for guiding adjuvant therapy and hence warrant further investigation.
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Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estudios Transversales , Femenino , Humanos , Pronóstico , Receptor ErbB-2/metabolismo , Factores de Riesgo , Trastuzumab/uso terapéutico , Resultado del TratamientoRESUMEN
The vast amount of reflectance information obtained from the hyperspectral imaging devices offers great opportunities for investigating the function and structure of human tissue. However, the captured hyperspectral data often contain various noises due to the intrinsic imperfection of associated electrical and optical imaging components. This work proposed an automatic total variation algorithm to suppress the noises while preserving the details of the spectral and spatial information. The variation of spectral images at neighboring bands was calculated for regulating the total variation of hyperspectral data so that the spectral-dependent noises can be treated differentially across all bands. Experimental results demonstrated that the proposed method could effectively remove the spectral noises, especially near the ends of those extreme bands. The noise suppressed hyperspectral data could then be used for the visualization enhancement on pathophysiological conditions of intraoperative observed anatomies such as the vessels of brain tissues.
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Algoritmos , Imagen Óptica , HumanosRESUMEN
Background: Identified as a hallmark of cancer, the dysregulated cell cycle progression plays an important role in the promotion and progression of lung adenocarcinoma (LUAD). However, the genomic and microenvironment differences between cell cycle progression pathway altered/non-altered LUAD patients remain to be elucidated. Materials and Methods: Data of this study were obtained from The Cancer Genome Atlas (TCGA), including simple nucleotide variation, copy number variation (CNV), RNA-seq gene expression, miRNA expression, survival, and clinical information. Besides, 34 LUAD samples from our institution were used as a validation cohort. Differentially expressed genes (DEGs), enrichment analysis, and immune cell infiltration were detected. At last, we built a LASSO-binary Logistic regression model to predict the cell-cycle-related gene mutation (CDKN2A, CCND1, CDK4, CCNE1, and RB1) in LUAD patients and further verified it in the samples from our institution. Results: Based on the cell cycle progression pathway status, the LUAD patients were divided into the mutation (n=322) and wild (n=46) groups. Compared to the wild group, the mutation group had a higher mutational load and CNV. Among the 16684 protein-coding genes analyzed, 302 were upregulated, and 354 were downregulated in the mutation group. Enrichment analysis indicated that these DEGs were closely related to metabolism items. After performing immune cell infiltration analysis of 22 immune cells, we found the proportion of 5 immune cells such as monocytes (P<0.01) and dendritic cells (P<0.01) were higher in the wild group. Finally, a cell-cycle-related 15-signature model was built by LASSO-Logistic regression analysis, which could predict the cell cycle progression pathway-related gene mutation (CDKN2A, CCND1, CDK4, CCNE1, and RB1) in LUAD patients. The validation cohorts showed the sensitivity and specificity of this model were 0.667 and 0.929, respectively. Conclusion: The genomic and microenvironment characteristics differed between the cell cycle progression pathway altered/non-altered patients with LUAD. Our findings may provide new insight into personalized treatment for LUAD patients.
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A numerical approach has been proposed to identify bands for optimally estimating the concentration of three types of viable chromophores within biological tissue. The bands are determined according to the condition number of absorption matrix associated with the attenuation coefficients of chromophores. The effectiveness of different sets of selected band combination was verified by using the spectral reflectance images of skin tissue acquired from standard forearm vascular occlusion tests via a spectroradiometer. Experimental results demonstrated that the concentration of chromophores within skin tissue could be estimated correctly and robustly only when the bands were deliberately selected.
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Piel , Piel/diagnóstico por imagenRESUMEN
Trastuzumab is the only approved targeted drug for first-line treatment of HER2-positive advanced gastric cancer, but the high rate of primary resistance and rapid emergence of secondary resistance limit its clinical benefits. We found that trastuzumab-resistant (TR) gastric cancer cells exhibited high glycolytic activity, which was controlled by hexokinase 2 (HK2)-dependent glycolysis with a circadian pattern [higher at zeitgeber time (ZT) 6, lower at ZT18]. Mechanistically, HK2 circadian oscillation was regulated by a transcriptional complex composed of PPARγ and the core clock gene PER1. In vivo and in vitro experiments demonstrated that silencing PER1 disrupted the circadian rhythm of PER1-HK2 and reversed trastuzumab resistance. Moreover, metformin, which inhibits glycolysis and PER1, combined with trastuzumab at ZT6, significantly improved trastuzumab efficacy in gastric cancer. Collectively, these data introduce the circadian clock into trastuzumab therapy and propose a potentially effective chronotherapy strategy to reverse trastuzumab resistance in gastric cancer. SIGNIFICANCE: In trastuzumab-resistant HER2-positive gastric cancer, glycolysis fluctuates with a circadian oscillation regulated by the BMAL1-CLOCK-PER1-HK2 axis, which can be disrupted with a metformin-based chronotherapy to overcome trastuzumab resistance.
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Hexoquinasa , Metformina , Proteínas Circadianas Period , Neoplasias Gástricas , Ritmo Circadiano/genética , Hexoquinasa/genética , Humanos , Proteínas Circadianas Period/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/farmacología , Trastuzumab/uso terapéuticoRESUMEN
Due to the aggregation-caused quenching effect and near-infrared I poor penetration capabilities of common fluorescent molecules, their applications in visualized imaging and photoactivated treatment are limited. Therefore, new near-infrared II (NIR-II) molecule (named TST), which had the abilities of aggregation-induced emission (AIE) and photothermal therapy are synthesized. Moreover, in order to further improve its fluorescent yield and therapeutic effect, camptothecin prodrug (CPT-S-PEG) and novel immune checkpoint inhibitor AZD4635 are used to co-assemble with TST into nanoparticles for drug delivery. On account of the strong interaction of camptothecin and TST, the intramolecular rotation of TST is limited, thereby inhibiting non-radiation attenuation and promoting fluorescence generation when the nanoparticles are intact. As nanoparticles uptake by cancer cells, redox sensitive CPT-S-PEG is degraded and the nanoparticles disintegrate. The released TST enhances non-radiative attenuation and expedites photothermal conversion because of the removal of the constraint of camptothecin. Furthermore, photothermal therapy induces immunogenic cell death of cancer cells and releases abundant ATP into the tumor microenvironment to recruit immune cells. However, superfluous ATP is converted into immunosuppressive adenosine through the CD39-CD73-A2AR pathway. The AZD4635 released by photothermal disintegration of the nanoparticles just blocks this pathway timely, achieving favorable synergistic effect of photothermal therapy, chemotherapy, and immunotherapy.
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Nanopartículas , Profármacos , Inmunoterapia , Nanopartículas/uso terapéutico , Fototerapia/métodos , Terapia Fototérmica , Profármacos/farmacologíaRESUMEN
Background: Ferroptosis is a newly identified regulated cell death characterized by iron-dependent lipid peroxidation and subsequent membrane oxidative damage, which has been implicated in multiple types of cancers. The multi-omics differences between cancer cell lines with high/low ferroptosis scores remain to be elucidated. Methods and Materials: We used RNA-seq gene expression, gene mutation, miRNA expression, metabolites, copy number variation, and drug sensitivity data of cancer cell lines from DEPMAP to detect multi-omics differences associated with ferroptosis. Based on the gene expression data of cancer cell lines, we performed LASSO-Logistic regression analysis to build a ferroptosis-related model. Lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), esophageal cancer (ESCA), bladder cancer (BLCA), cervical cancer (CESC), and head and neck cancer (HNSC) patients from the TCGA database were used as validation cohorts to test the efficacy of this model. Results: After stratifying the cancer cell lines into high score (HS) and low score (LS) groups according to the median of ferroptosis scores generated by gene set variation analysis, we found that IC50 of 66 agents such as oxaliplatin (p < 0.001) were significantly different, among which 65 were higher in the HS group. 851 genes such as KEAP1 and NRAS were differentially muted between the two groups. Differentially expressed genes, miRNAs and metabolites were also detected-multiple items such as IL17F (logFC = 6.58, p < 0.001) differed between the two groups. Unlike the TCGA data generated by bulk RNA-seq, the gene expression data in DEPMAP are from pure cancer cells, so it could better reflect the traits of tumors in cancer patients. Thus, we built a 15-signature model (AUC = 0.878) based on the gene expression data of cancer cell lines. The validation cohorts demonstrated a higher mutational rate of NFE2L2 and higher expression levels of 12 ferroptosis-related genes in HS groups. Conclusion: This article systemically analyzed multi-omics differences between cancer cell lines with high/low ferroptosis scores and a ferroptosis-related model was developed for multiple cancer types. Our findings could improve our understanding of the role of ferroptosis in cancer and provide new insight into treatment for malignant tumors.