Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity.

Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in the brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to the M2 phenotype via the α2ß1 integrin/nuclear factor κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8+ T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8+ T cells and abolishes BrM. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrM-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression and that blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors.

FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing.

Mesenchymal glioblastoma (GBM) is highly resistant to radio-and chemotherapy and correlates with worse survival outcomes in GBM patients; however, the underlying mechanism determining the mesenchymal phenotype remains largely unclear. Herein, it is revealed that FBXO7, a substrate-recognition component of the SCF complex implicated in the pathogenesis of Parkinson's disease, confers mesenchymal properties and chemoresistance in GBM by controlling Rbfox2-mediated alternative splicing. Specifically, FBXO7 ubiquitinates Rbfox2 Lys249 through K63-linked ubiquitin chains upon arginine dimethylation at Arg341 and Arg441 by PRMT5, leading to Rbfox2 stabilization. FBXO7 controls Rbfox2-mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion of FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, thereby upregulates CD44, CD9, and ID1 levels, resulting in GBM stem cell self-renewal and mesenchymal transformation. Moreover, FBXO7 is stabilized by temozolomide, and FBXO7 depletion sensitizes tumor xenografts in mice to chemotherapy. The findings demonstrate that the FBXO7-Rbfox2 axis-mediated splicing contributes to mesenchymal transformation and tumorigenesis, and targeting FBXO7 represents a potential strategy for GBM treatment.

SEC61G assists EGFR-amplified glioblastoma to evade immune elimination.

Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that SEC61G is always coamplified with EGFR and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8+ T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of EGFR-amplified GBMs.

Derepression of the USP22-FASN axis by p53 loss under oxidative stress drives lipogenesis and tumorigenesis.

Overproduction of reactive oxygen species (ROS) and aberrant lipid metabolism are established hallmarks of cancer; however, the role of ROS in lipid synthesis during tumorigenesis is almost unknown. Herein, we show that ROS regulates lipid synthesis and thus controls colorectal tumorigenesis through a p53-dependent mechanism. In p53 wild-type colorectal cancer (CRC) cells, hydrogen peroxide (H2O2)-induced p53 expression represses the transcription of deubiquitinase USP22, which otherwise deubiquitinates and stabilizes Fatty Acid Synthase (FASN), and thus inhibits fatty acid synthesis. Whereas, in p53-deficient CRC cells, ROS-mediated inhibition of USP22 is relieved, leading to FASN stabilization, which thus promotes lipid synthesis and tumor growth. In human CRC specimens, USP22 expression is positively correlated with FASN expression. Our study demonstrates that ROS critically regulates lipid synthesis and tumorigenesis through the USP22-FASN axis in a p53-dependent manner, and targeting the USP22-FASN axis may represent a potential strategy for the treatment of colorectal cancer.

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma.

Background: Pyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas. Methods: The TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated. Results: Patients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P<0.001) and progression-free survival time (P<0.001) than Cluster 1. CD8+ T cell enrichment was observed in Cluster 1. A pyroptosis-related risk signature (PRRS) was then established. The high PRRS group showed a significantly poorer prognosis than the low PRRS group in the training cohort (P<0.001), with validation in the internal and external validation cohorts. Immunohistochemical staining demonstrated that CD8+ T cells were enriched in high PRRS glioma tissues. PRRS genes also showed cell-specific expression in tumor and immune cells. Moreover, the high PRRS risk group showed higher temozolomide sensitivity and increased response to anti-PD1 treatment in a glioblastoma immunotherapy cohort. Finally, Bcl-2 inhibitors were screened as candidates for adjunct immunotherapy of gliomas. Conclusion: The pyroptosis-related signature established in this study can be used to reliably predict clinical outcomes and immunotherapy responses in glioma patients. The correlation between the pyroptosis signature and the tumor immune microenvironment may be used to further guide the sensitization of glioma patients to immunotherapy.