《癌细胞》：预测癌症的耐药性具有深远意义

资讯作者：The Flanders Institute for Biotechnology(VIB)

编辑翻译：奇奇

译文校对：菁菁

文献于2021年6月发表在美国著名医学期刊《癌细胞》（Cancer Cell）上。文献中VIB的研究人员探索了癌症对抗癌药物的耐药性的途径，发现与某些干细胞有关，该发现对抗癌药物的研究具有深远意义。

癌细胞可以通过遗传和非遗传机制对治疗产生耐药性。但是目前还不清楚这些耐药性途径中的一种是如何以及为什么生效的。了解癌细胞的这种“选择”可能有助于我们设计出更好的治疗策略。如今，Jean-Christophe Marine教授的团队(来自VIB-KU Leuven癌症生物学中心)表示，某些干细胞的存在与非遗传抗性机制的发展相关。他们的研究发表在著名的《癌细胞》杂志上。

耐药性的两种途径

尽管癌症治疗在过去几年中取得了很大的进步，但是耐药性仍然是一个主要问题。当癌细胞对靶向药物产生耐药性时，即便患者正在接受治疗，癌细胞还是能够继续扩散。

直到最近，人们还认为这种耐药性完全是通过癌细胞中的突变(基因改变)产生的。然而，新的研究表明，抗癌药物的耐药性也是可以通过非遗传机制产生的，这种机制可以在不改变DNA序列的情况下改变某些基因的表达。

Marine教授解释说，“非基因重编程作为治疗耐药性驱动因素的重要性在该领域尚未被广泛接受。虽然我的团队已经证明药物耐受性可以由非遗传机制驱动，但仍然缺乏可以证明在没有遗传原因的情况下也可以获得耐药性的强有力证据。”

在他们的研究中，Marine教授的团队坚定地认为非遗传机制导致黑色素瘤治疗的耐药性。关键问题已经变成了“癌细胞如何在不同的耐药性途径中‘选择’?”

神经峭干细胞是关键

令人惊讶的是，该团队证明耐药途径是预先确定的，而不是随机选择的。他们发现，一组特定细胞群（神经嵴干细胞）的存在导致了黑色素瘤的非遗传性耐药性，而不是遗传性耐药性。一个可能的原因是，这些神经嵴干细胞表现出“表观遗传可塑性”，这意味着这些细胞有更强的能力来选择它们表达哪些基因以及表达程度。这些细胞通过自我重组来规避治疗压力。

研究人员还确定了促使神经嵴干细胞出现并促进其生存的信号通路。该信号通路关键取决于蛋白黏着斑激酶(Focal Adhesion Kinase，FAK)。通过抑制这种蛋白的活性，该团队能够大大减少移植到小鼠体内的异种肿瘤细胞（来自人类患者）的非遗传耐药性的发生。

这种对肿瘤细胞生物学的新基本见解和最近发现的对癌症药物的非遗传耐药性机制的结合具有深远的临床影响。

参与该项研究的高级博士后Florian Rambow解释说:“这些发现具有几个重要的临床意义。我们不仅展示了一种抑制非遗传抗性的可行方法，而且还证明了特定细胞的存在决定了可能发生的抗性机制。这项观察是预测患者潜在耐药途径和开展个性化治疗的关键。”

英文原文

Predicting Resistance to Anticancer Drugs

Cancer cells can develop resistance to therapy through both genetic and non-genetic mechanisms. But it is unclear how and why one of these routes to resistance prevails. Understanding this ‘choice’by the cancer cells may help us devise better therapeutic strategies. Now, the team of Prof. Jean-Christophe Marine (VIB-KU Leuven Center for Cancer Biology)shows that the presence of certain stem cells correlates with the development of nongenetic resistance mechanisms. Their study is published in the prestigious journal Cancer Cell.

Two routes to resistance

Even though cancer therapy has made greatstrides in the last few years, resistance remains a major problem. When cancer cells develop resistance against the drugs targeting them, they can continue to spread, even when the patient is going through therapy.

Until recently, it was thought that this resistance arises exclusively through mutations—genetic alterations—in the cancer cells. However, new studies have suggested that resistance against cancer drugs can also arise via non-genetic mechanisms that change the expression of certain genes without altering the DNA sequence.

Prof. Marine explains that "the importance of nongenetic reprogramming as a driver of therapy resistance is notyet widely accepted in the field. Although my group has demonstrated that drug tolerance can be driven by nongenetic mechanisms, strong evidence that resistance can be acquired in absence of a genetic cause is still lacking."

In their study, the team of Prof. Marine firmly establishes that nongenetic mechanisms contribute to resistance to therapy in melanoma. The key question has become "how do cancer cells ‘choose’ between the different routes to resistance?"

Neural crest stem cells as key

Surprisingly, the team demonstrates that the road to resistance is predetermined and not randomly selected. They show that the presence of a specific group of cells, neural crest stem cells, leads to non-genetic rather than genetic drug resistance in melanoma. A possible reason for this is that these neural crest stem cells exhibit ‘epigenetic plasticity’, which means that these cells have an increased ability to select which genes they express and how much. These cells literally reprogram themselves to evade the therapeutic pressure.

The researchers also identified the signaling pathway that drives the emergence of the neural crest stem cells and promotes their survival. This signaling pathway depends crucially on the protein Focal Adhesion Kinase (or FAK). By blocking the activity of this protein, the team was able to drastically reduce the occurrence of non-genetic drug resistance in patient-derived xenografts—tumor cells from human patients that were implanted in mice.

This combination of new basic insights into tumor cell biology and recently discovered non-genetic resistance mechanisms to cancer drugs has far-reaching clinical consequences.

Florian Rambow, senior postdoc who contributed to the study, explains that "these findings have several important clinical implications. Not only did we show a viable way to suppress non-genetic resistance, but we also demonstrated that the presence of specific cells dictates which resistance mechanism is likely to occur. This observationis the key to predicting potential resistance routes in patients and developing personalized therapies."

参考文献 

Oskar Marin-Bejar et al, Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma, Cancer Cell (2021). DOI: 10.1016/j.ccell.2021.05.015

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