Francis Jeffrey C, Capper Amy, Ning Jian, Knight Eleanor, de Bono Johann, Swain Amanda
Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
Tumour Profiling Unit, The Institute of Cancer Research, London SW3 6JB, UK.
Oncotarget. 2018 Jan 10;9(7):7604-7615. doi: 10.18632/oncotarget.24123. eCollection 2018 Jan 26.
Aggressive lethal prostate cancer is characterised by tumour invasion, metastasis and androgen resistance. Understanding the mechanisms by which localised disease progresses to advanced lethal stages is key to the development of effective therapies. Here we have identified a novel role for the transcription factor, SOX9, as a driver of aggressive invasive prostate cancer. Using genetically modified mouse models, we show that increased expression in the prostate epithelia of animals with loss leads to a highly invasive phenotype and metastasis. In depth analysis of these mice and related models reveals that SOX9 acts a key regulator of various processes that together promote tumour progression. We show that this factor promotes cell lineage plasticity with cells acquiring properties of basal stem cells and an increase in proliferation. In addition, increased SOX9 leads to changes in cytoskeleton and adhesion, deposition of extracellular matrix and epithelia to mesenchyme transition, properties of highly invasive cells. Analysis of castrated mice showed that the invasive phenotype driven by SOX9 is independent of androgen levels. Our study has identified a novel driver of prostate cancer progression and highlighted the cellular and molecular processes that are regulated by to achieve invasive disease.
侵袭性致死性前列腺癌的特征是肿瘤侵袭、转移和雄激素抵抗。了解局限性疾病进展为晚期致死阶段的机制是开发有效治疗方法的关键。在此，我们确定了转录因子SOX9在侵袭性前列腺癌发展过程中的新作用。通过基因改造小鼠模型，我们发现，在缺失的动物前列腺上皮细胞中SOX9表达增加会导致高度侵袭性表型和转移。对这些小鼠及相关模型的深入分析表明，SOX9是共同促进肿瘤进展的各种过程的关键调节因子。我们发现，该因子可促进细胞谱系可塑性，使细胞获得基底干细胞特性并增加增殖。此外，SOX9表达增加会导致细胞骨架和黏附的变化、细胞外基质的沉积以及上皮-间质转化，这些都是高侵袭性细胞的特性。对去势小鼠的分析表明，由SOX9驱动的侵袭性表型与雄激素水平无关。我们的研究确定了前列腺癌进展的一个新驱动因素，并突出了由SOX9调控以实现侵袭性疾病的细胞和分子过程。
