Wnt signaling-mediated activation of cancer cell stemness in thoracic SMARCA4-deficient undifferentiated tumor cells.

IF 10.4 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2026-06-30 DOI:10.1038/s41420-026-03224-6

Yan Xu, Lumei Wang, Hongjia Zhang, Lin Liang, Hui Han, Tianyu Xiao, Cheng Zhang, Qiye He, Zuoren Yu, Jinli Gao

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引用次数: 0

Abstract

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) represent a distinct and highly aggressive malignancy characterized by SMARCA4 deficiency, poor prognosis, and resistance to chemotherapy. The lack of clarity regarding the regulatory mechanisms underlying this disease has hindered the development of standardized treatment guidelines. In this study, we analyzed clinical samples and found significantly elevated levels of cancer stem cell markers, including SOX2, CD34, c-Myc, and EpCam, in thoracic SMARCA4-UT, which were further confirmed in SMARCA4-deficient non-small cell lung cancer (NSCLC) cells. Furthermore, SMARCA4 knockdown in NSCLC cells promoted cell proliferation, migration, invasion, and tumorsphere formation in vitro, as well as enhanced tumor growth in a mouse model in vivo. RNA sequencing analysis of SMARCA4-deficient cells revealed the upregulation of a subset of genes, including Wnt10A, and activation of Wnt signaling. This was validated through SMARCA4-ChIP-seq and SMARCA4-ChIP-PCR analyses, Wnt activity reporter assays, and subcellular distribution analysis of β-catenin. Subsequent studies using a small molecule Wnt inhibitor in SMARCA4-deficient cells and thoracic SMARCA4-UT patient-derived organoids demonstrated induction of apoptosis, inhibition of cell stemness, and suppression of tumor cell growth. These results suggest the potential for developing a novel therapeutic strategy targeting cancer stem cells for the treatment of thoracic SMARCA4-UT.

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Wnt信号介导的胸腔smarca4缺陷未分化肿瘤细胞的癌细胞干细胞活化。

胸部SMARCA4缺陷未分化肿瘤（SMARCA4- ut）是一种独特的、高度侵袭性的恶性肿瘤，其特征是SMARCA4缺陷、预后差和化疗耐药。这种疾病背后的调控机制缺乏明确性，阻碍了标准化治疗指南的制定。在本研究中，我们分析了临床样本，发现胸腔SMARCA4-UT中癌症干细胞标志物SOX2、CD34、c-Myc和EpCam水平显著升高，这在smarca4缺陷的非小细胞肺癌（NSCLC）细胞中得到进一步证实。此外，在体外实验中，在NSCLC细胞中敲低SMARCA4可促进细胞增殖、迁移、侵袭和肿瘤球形成，并在体内小鼠模型中促进肿瘤生长。对smarca4缺陷细胞的RNA测序分析显示，包括Wnt10A在内的一组基因上调，并激活Wnt信号。通过SMARCA4-ChIP-seq和SMARCA4-ChIP-PCR分析、Wnt活性报告基因分析和β-catenin亚细胞分布分析验证了这一点。随后的研究表明，在smarca4缺陷细胞和胸椎SMARCA4-UT患者衍生的类器官中使用小分子Wnt抑制剂可诱导细胞凋亡，抑制细胞干性，抑制肿瘤细胞生长。这些结果表明，开发一种针对癌症干细胞治疗胸部SMARCA4-UT的新治疗策略具有潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.