Cell子刊:研究发现最常见胰腺癌的新治疗靶点!

2022-05-23 转化医学网 网络

研究结果表明,抑制ISL2表观遗传沉默下游的通路可能是一个有希望的治疗靶点。

导读:胰腺导管腺癌(PDA)生存率很低,PDA肿瘤含有致密的组织,癌细胞不断地重新编程其DNA转录和代谢功能,以在肿瘤的恶劣微环境中生存。近期研究发现了一种针对PDA的潜在治疗靶点,转录因子ISL2可以作为PDA肿瘤的肿瘤抑制因子,并且它的缺失可以重新编程PDA细胞的转录和代谢状态。

根据发表在《Developmental Cell》上的一项研究“ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer”,Northwestern Medicine研究者发现了一种针对最常见类型胰腺癌的潜在治疗靶点。

https://www.cell.com/developmental-cell/fulltext/S1534-5807(22)00254-4

研究结果表明,转录因子ISL2可以作为胰腺导管腺癌(PDA)肿瘤的肿瘤抑制因子,并且它的缺失可以重新编程PDA细胞的转录和代谢状态。

“ISL2状态可能是一种精准医学方法,我们可以检查肿瘤,观察ISL2水平,然后确定这些肿瘤是否更依赖于脂质代谢,或者我们是否应该在这些类型的肿瘤中抑制这条通路,”Mazhar Adli博士说。

PDA的生存率很低——超过80%的患者是在癌症晚期和肿瘤不再符合手术切除条件时确诊的。诊断后,患者的平均生存期通常为4-6个月。从本质上讲,PDA肿瘤含有致密的组织,癌细胞不断地重新编程其DNA转录和代谢功能,以在肿瘤的恶劣微环境中生存。

Adli说:“目前,我们对是什么驱动了胰腺癌的初始阶段有了相当好的了解,但在这些初始阶段之后,是什么使这些胰腺癌细胞变得如此具有可塑性并在不同的微环境中生存却知之甚少。”

利用无偏倚的全基因组CRISPR-Cas9筛选,研究者在小鼠中研究了PDA肿瘤细胞系,以鉴定可能参与PDA细胞生长和增殖的转录因子和染色质调控因子。

在表观遗传水平上,他们发现ISL2在原发性PDA肿瘤中通过DNA甲基化沉默。值得注意的是,以高DNA甲基化为ISL2位点的PDA肿瘤具有更多的侵袭行为,这与患者生存率低有关。与正常肿瘤旁组织相比,大多数PDA肿瘤在ISL2位点具有更高水平的DNA甲基化,这表明ISL2在大多数胰腺肿瘤中表观遗传学上是“沉默的”。

研究者发现,用基于CRISPR的表观遗传编辑增加ISL2表达可降低PDA细胞增殖。此外,他们还发现ISL2水平低的细胞具有更高的执行氧化磷酸化的能力,这一过程中细胞更喜欢氧化脂质和线粒体中的其他代谢产物以维持其生物能量需求,而不是代谢葡萄糖。Adli说:“这是一个令人惊讶的发现,因为大多数癌细胞偏好葡萄糖,但最近的研究证明,存在实际上更依赖于氧化磷酸化的癌细胞亚群,我们认为ISL2是这一动态过程的调节因子之一。”体内和体外PDA肿瘤细胞的高级分子谱分析也发现,ISL2缺失的PDA细胞可能对靶向线粒体复合物I的特异性抑制剂或氧化磷酸化发生的地方敏感。

总的来说,研究结果表明,抑制ISL2表观遗传沉默下游的通路可能是一个有希望的治疗靶点。Adli说:“这表明可能ISL2在空间上调控了这种基因表达程序,从而使胰腺癌细胞具有这种可塑性,并在这种环境中生存。这项研究是第一篇将ISL2定性为一种新型肿瘤抑制因子的全面出版物,我们希望我们的研究小组和其他人继续更多地了解这种似乎正在发挥非常关键作用的变化。”

 

参考资料:

https://medicalxpress.com/news/2022-05-therapeutic-common-pancreatic-cancer.html

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    2022-05-23 ms5000000518166734

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