Journal of Extracellular Vesicles
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2023
·Vol. 12
·期 2
·e12310
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IF 16
Xiaoning Wang,Ruoyi Wu,Peisong Zhai,Zheqi Liu,Ronghui Xia,Zhen Zhang,Xing Qin,Chuwen Li,Wantao Chen,Jiang Li,Jianjun Zhang
Tumour cells under hypoxia tend to modulate the number and contents of extracellular vesicles (EVs) to regulate the tumour microenvironment (TME) and thus promote tumour progression. However, the mechanism of how hypoxia influences the secretion of EVs remains to be elucidated. Here, we confirm the increased production of EVs in head and neck squamous cell carcinoma (HNSCC) cells under hypoxia, where endosome-derived EVs are the main subtype affected by insufficient O 2 . The accumulation of hypoxia-inducible factor-1α (HIF-1α) under hypoxia directly downregulates the expression of ATP6V1A, which is pivotal to maintain the homeostasis of lysosomes. Subsequently, impaired lysosomal degradation contributes to the reduced fusion of multivesicular bodies (MVBs) with lysosomes and enables the secretion of intraluminal vesicles (ILVs) as EVs. These findings establish a HIF-1α-regulated lysosomal dysfunction-EV release axis and provide an exquisite framework to better understand EV biogenesis.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF CELL BIOLOGY
·
2026
·Vol. 105
·期 3
·151555
·
IF 4.3
Huixia Li,Taoran Xie,David YLChan,Ellis Kin Lam Fok,Liandong Zuo,Gangcai Xie,Qianqian Sha,Hao Chen
Epididymal epithelial cells are critical for sperm maturation. Although previous studies have determined the development of epididymal epithelial cells in rat epididymis, the postnatal developmental trajectories of distinct epithelial cell types in the mouse epididymis remain elusive. Here, we examined the developmental timeline of mouse epididymal epithelium differed from that of the rat by confocal immunostaining and single-cell RNA sequencing (scRNA-seq). In mice, principal and basal cells appeared as early as postnatal day 7 (PD7) across all segments, labeled by AQP9 and KRT5, in contrast to the later emergence in rats (e.g., basal cells at PD14 in rat cauda). ATP6V1A-positive clear cells were detected at PD28 in caput, corpus, and cauda but not in the initial segment, while narrow cells were observed in all segments beginning at PD14. These contrasted with the rat, in which clear cells appeared at PD14. Notably, scRNA-seq and immunostaining identified a previously unrecognized KRT5⁺/ATP6V1A⁺ narrow-like basal cell subpopulation, enriched in lysosomes and mainly localized to the caput and corpus. These findings revealed an earlier epithelial maturation in mice compared to rats, underscoring the importance of choosing animal models. The newly identified basal subpopulation may contribute to luminal acidification and homeostasis, offering new insights into epididymal physiology and reproductive biology.
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高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-16
·
IF 11.4
Li Xing,Sun Shiyu,Zhang Wansong,Liang Ziwei,Fang Yitong,Sun Tianhu,Wan Yong,Ma Xingcong,Zhang Shuqun,Xu Yang,Tian Ruilin
Background Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM. Methods We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 MG cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 MG cells. Results We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4 , PI4KA , ATP6V1A , UBA1 , and NDUFV1 , that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy. Conclusions Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.
CAS / MDL:
研究领域:
肿瘤学
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免疫学
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基因组学
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细胞生物学
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高影响因子
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