DNA Methyltransferase 3B-Mediated Intratumoral Heterogeneity and Therapeutic Targeting in Breast Cancer Recurrence and Metastasis.
DNA Methyltransferase 3B-Mediated Intratumoral Heterogeneity and Therapeutic Targeting in Breast Cancer Recurrence and Metastasis.
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DOI：
10.1158/1541-7786.mcr-21-0887
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发表时间：
2022-11-03
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癌细胞如何被选择和进化以建立远处转移集落的机制尚不清楚。肿瘤的异质性和缺乏生物标志物是癌症生物学和治疗中最困难的挑战。在小鼠三阴性乳腺癌转移模型中，我们报告了DNA甲基转移酶3B （DNMT3B）在小鼠和人类原发肿瘤中的异质表达。在多个人类乳腺癌数据集中，高水平的DNMT3B与不良的临床结果相关。从机制上说，DNMT3B （DNMT3BH）含量高的克隆细胞表现出更高的波形蛋白（VIM）表达，并表现出增强的上皮-间质转化（EMT）能力。VIM的缺失减少了DNMT3BH细胞的转移表型。重要的是，在原发肿瘤手术切除的临床前小鼠模型中，围手术期靶向DNMT3B联合化疗可显著抑制肿瘤复发和转移。我们的研究发现DNMT3B介导的转录调控是肿瘤异质性的重要介质，并表明DNMT3B对肿瘤侵袭和转移至关重要，这增强了其作为治疗转移性疾病靶点的潜力。我们发现DNMT3B介导的转录组变化为肿瘤内异质性和化疗耐药提供了新的机制见解，DNMT3B联合化疗的治疗靶向性为转移性疾病特别是TNBC患者提供了额外的治疗选择。
The mechanisms of how cancer cells are selected and evolve to establish distant metastatic colonies remain unclear. Tumor heterogeneity and lack of biomarkers are some of the most difficult challenges in cancer biology and treatment. Here using mouse models for triple negative breast cancer metastasis, we report heterogeneous expression of DNA methyltransferase 3B (DNMT3B) in both mouse and human primary tumors. High levels of DNMT3B were correlated with poor clinical outcomes in multiple human breast cancer datasets. Mechanistically, clonal cells with high DNMT3B (DNMT3BH) showed higher vimentin (VIM) expression and displayed enhanced epithelial-to-mesenchymal transition (EMT) capacity. Deletion of VIM diminished the metastatic phenotype of DNMT3BH cells. Importantly, in preclinical mouse models in which the primary tumors were surgically removed, perioperative targeting of DNMT3B in combination with chemotherapy markedly suppressed tumor recurrence and metastasis. Our studies identify DNMT3B-mediated transcription regulation as an important mediator of tumor heterogeneity and show that DNMT3B is critical for tumor invasion and metastasis, reinforcing its potential as a target for treating metastatic disease. Our findings of transcriptome changes mediated by DNMT3B provide new mechanistic insight for intra-tumor heterogeneity and chemo-resistance, and therapeutic targeting of DNMT3B in combination with chemotherapy offer additional treatment options for metastatic disease especially for TNBC patients.