RESUMO
Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.
Assuntos
Linfoma Anaplásico de Células Grandes , Linfoma Anaplásico Cutâneo Primário de Células Grandes , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico/genética , Interleucinas/metabolismoRESUMO
Extracellular matrix protein 2 (ECM2), which regulates cell proliferation and differentiation, has recently been reported as a prognostic indicator for multiple cancers, but its value in lower grade glioma (LGG) remains unknown. In this study, LGG transcriptomic data of 503 cases in The Cancer Genome Atlas (TCGA) database and 403 cases in The Chinese Glioma Genome Atlas (CGGA) database were collected to analyze ECM2 expression patterns and the relationship with clinical characteristics, prognosis, enriched signaling pathways, and immune-related markers. In addition, a total of 12 laboratory samples were used for experimental validation. Wilcoxon or Kruskal-Wallis tests demonstrated highly expressed ECM2 in LGG was positively associated with malignant histological features and molecular features such as recurrent LGG and isocitrate dehydrogenase (IDH) wild-type. Also, Kaplan-Meier (KM) curves proved high ECM2 expression could predict shorter overall survival in LGG patients, as multivariate analysis and meta-analysis claimed ECM2 was a deleterious factor for LGG prognosis. In addition, the enrichment of immune-related pathways for ECM2, for instance JAK-STAT pathway, was obtained by Gene Set Enrichment Analysis (GSEA) analysis. Furthermore, positive relationships between ECM2 expression with immune cells infiltration and cancer-associated fibroblasts (CAFs), iconic markers (CD163), and immune checkpoints (CD274, encoding PD-L1) were proved by Pearson correlation analysis. Finally, laboratory experiments of RT-qPCR and immunohistochemistry showed high expression of ECM2, as well as CD163 and PD-L1 in LGG samples. This study identifies ECM2, for the first time, as a subtype marker and prognostic indicator for LGG. ECM2 could also provide a reliable guarantee for further personalized therapy, synergizing with tumor immunity, to break through the current limitations and thus reinvigorating immunotherapy for LGG. AVAILABILITY OF DATA AND MATERIALS: Raw data from all public databases involved in this study are stored in the online repository (chengMD2022/ECM2 (github.com)).
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Antígeno B7-H1 , Janus Quinases , Prognóstico , Fatores de Transcrição STAT , Transdução de Sinais , Glioma/genética , Glioma/terapia , Imunoterapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapiaRESUMO
Macrophages are the most abundant immune cells in primary and metastatic tumor tissues. Studies have shown that macrophages mainly exhibit a tumor-promoting phenotype and play a key role in tumor progression and metastasis. Therefore, many macrophage-targeted drugs have entered clinical trials. However, compared to preclinical studies, some clinical trial results showed that macrophage-targeted therapy did not achieve the desired effect. This may be because most of what we know about macrophages comes from in vitro experiments and animal models, while macrophages in the more complex human microenvironment are still poorly understood. With the development of technologies such as single-cell RNA sequencing, we have gained a new understanding of the origin, classification and functional mechanism of tumor-associated macrophages. Therefore, this study reviewed the recent progress of macrophages in promoting tumor progression and metastasis, aiming to provide some help for the formulation of optimal strategies for macrophage-targeted therapy.
Assuntos
Neoplasias , Animais , Humanos , Neoplasias/terapia , Macrófagos/patologia , Sistemas de Liberação de Medicamentos , Microambiente TumoralRESUMO
HOXA4 is a novel oncogene that has been observed in many kinds of tumors, but its role during glioma carcinogenesis and its clinical significance in diagnosing and prognosis human glioma remains unknown. In the present study, the Chinese Glioma Atlas (CGGA)-RNA sequencing database, CGGA microarray, and The Cancer Genome Atlas (TCGA)-RNA seq data from 1674 glioma patients were obtained from online databases and analyzed using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) to detect changes in the expression level of HOXA4 and characterize the relationship between HOXA4 and the clinical characteristics and prognosis of patients with glioma. Gene set enrichment analysis (GSEA) was used to reveal how HOXA4 regulates tumor-related pathways. HOXA4 mRNA levels in glioma tissue were higher than those in adjacent brain tissue. HOXA4 expression was also closely related to the clinical and molecular characteristics of gliomas, such as tumor grade and isocitrate dehydrogenase (IDH) mutation. Functional enrichment analysis revealed that HOXA4 could regulate cancer-related signal pathways, such as Cell cycle, Cell adhesion molecules cams, and JAK/STAT signaling pathway. Results of in vitro experiments confirmed that knockdown of HOXA4 blocks the cell cycle pathway and inhibits the proliferation, invasion and chemotherapy resistance in gliomas. We concluded that HOXA4 was an independent risk factor for glioma and may have clinical diagnostic potential. Meanwhile, our findings revealed that HOXA4 could be used as a biomarker for glioma diagnosis and treatment.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Isocitrato Desidrogenase/genética , Mutação/genética , Oncogenes , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genéticaRESUMO
Despite the growing recognition of ITGB3BP as an essential feature of various cancers, the relationship between ITGB3BP and glioma remains unclear. The main aim of this study was to determine the prognostic and diagnostic value of ITGB3BP in glioma. RNA-Seq and microarray data from 2222 glioma patients were included, and we found that the expression level of ITGB3BP in glioma tissues was significantly higher than that in normal brain tissues. Moreover, ITGB3BP can be considered an independent risk factor for poor prognosis and has great predictive value for the prognosis of glioma. Gene Set Enrichment Analysis results showed that ITGB3BP contributes to the poor prognosis of glioma by activating tumour-related signalling pathways. Some small-molecule drugs were identified, such as hexestrol, which may specifically inhibit ITGB3BP and be useful in the treatment of glioma. The TIMER database analysis results revealed a correlation between the expression of ITGB3BP and the infiltration of various immune cells in glioma. Our findings provide the first evidence that the up-regulation of ITGB3BP correlates with poor prognosis in human glioma. Thus, ITGB3BP is a potential new biomarker that can be used for the clinical diagnosis and treatment of glioma.
Assuntos
Neoplasias Encefálicas , Glioma , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioma/diagnóstico , Glioma/genética , Glioma/metabolismo , Humanos , Proteínas Nucleares/genética , Transdução de Sinais , Regulação para CimaRESUMO
The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.