哈佛科学家发现控制横纹肌瘤形成分子链

横纹肌样瘤是顽抗的儿童癌症之一，科学家们一直在寻找方法来了解是什么促使它们不屈不挠，使得他们无法接受治疗。

现在哈佛医学院、圣犹达儿童研究医院和其他地方的研究人员发现了干扰关键机制、调节细胞行为和控制肿瘤形成一系列事件的分子链。

横纹肌样瘤通常在肾脏中开始，但它们也可以出现或移动到脑和其他软组织中。虽然罕见，他们占儿科肾癌的不到2％ - 横纹肌瘤是高度致命的，生存率低于25％。

由多个团队研究的报告于12月12日在《自然遗传学》杂志上发表，描述了SMARCB1蛋白质的减少，如何破坏调节机制的工作，从而促进不受控制的恶性细胞增殖和横纹肌瘤的持续存活。

了解横纹肌样瘤细胞中不存在SMARCB1已经有一段时间，因此科学家怀疑它在癌症发展中发挥的作用。然而，它是如何做到，仍然是一个谜题。

新的发现提供了在那个谜题中缺少的一块，并揭示了SMARCB1的缺失如何解锁一系列事件，终导致细胞特性的丧失和细胞行为的深刻畸变。

“SMARCB1是称为SWI / SNF蛋白质复合物的关键组成部分，其主要充当肿瘤抑制剂。 SWI / SNF通过改变细胞核内的遗传物质包装来工作。这种改变是很重要的，因为它们使得DNA可接近导致基因表达的蛋白质，这是调节细胞行为和确定细胞身份的基本方式。

共同研究的资深作者、HMS生物医学信息学副教授Peter Park说，“我们的研究结果揭开了横纹肌肿瘤行为长期以来的神秘面纱。“他们揭示了SMARCB1如何变成重要的特性，开始危害表观遗传变化中扭曲的情节，通过改变细胞特性和燃料癌症形成。研究团队说，研究结果确定了可能的治疗目标，并为设计治疗提供了一个概念框架。

此外，该团队说，结果可能与其他形式的癌症有关。

共同资深作者、St.Jude综合癌症中心主任Charles Roberts说：“SWI / SNF复合物中的突变发生在人类众多的癌症中。因此，我们的研究结果不仅可以为横纹肌瘤提供深入见解。”

奇怪情况下无突变的肿瘤

在过去的十年中，癌症基因组测序的进展表明癌细胞具有非常高的基因突变率。这种可变性将肿瘤转化能够逃避药物治疗的可移行换影。但奇怪的是，与其他癌症的成百上千个突变相比，横纹肌肿瘤是具基因组稳定性和不可变的癌症，仅具有几个遗传突变。那么究竟是什么使这些不可变的肿瘤如此恶毒，研究人员想知道？

根据研究结果，答案似乎在肿瘤细胞的DNA和其表观基因组 - 位于DNA顶部的蛋白质和化学修饰剂的单层之外，并且可以深深地改变其行为。

癌症的急救包

这些见解阐明了一个关键的生存机制，允许横纹肌肿瘤逃脱身体的检查和控制。

在一系列患者衍生的横纹肌瘤组织的实验中，研究人员表明，SMARCB1的缺乏会影响SWI / SNF的功能。研究人员观察到SMARCB1的缺乏大幅降低了构成SWI / SNF复合物的其他几种蛋白质的水平，严重削弱了其调节能力。

具体来说，SMARCB1的缺失影响了SWI / SNF绑定遗传开关的能力，称为增强子 - 作为基因组调节剂的DNA片段，以确定哪些基因被打开，哪些基因保持休眠。

大约10000至20000个增强子在特定细胞的特定时间中开启。由于生物体中的所有细胞共享相同的DNA，这些遗传开关的活性对于决定细胞中哪些基因被激活以产生什么蛋白质至关重要。换句话说，增强子在决定特定细胞的特性和行为中起着至关重要的作用。

实验显示，SMARCB1的缺失导致许多常规增强子的调制基因表达和细胞行为失活，同时保持另一组增强子打开。研究人员认为，正是那些“增强子”可能对肿瘤生长和生存至关重要。

“如果在决定哪个增强子应该打开时发生错误，细胞就会失去其特性，”HMS的生物医学信息学的研究助理、共同研究员Burak Han Alvers说，他着重于表观遗传调控和转录。“在大多数的这种情况下，细胞会意识到有一个问题，并引发自我死亡。但是，在极少数情况下，增强子景观中的错误可导致癌症。这是我们观察到的在横纹肌瘤形成情况中发生的。

研究人员说，找到一种关闭剩余的活性增强子的方法可能是治疗横纹肌肿瘤铠甲的办法，并为其提供治疗的目标。

在后的概念验证步骤中，科学家在来自患者肿瘤的细胞系中恢复SMARCB1。肿瘤细胞系停止生长，这一发现强调了蛋白质在抑制肿瘤形成中的作用，该团队说。（来源：哈佛医学院  编译：麻省医疗国际 漆琳）

Agent of Mischief

By EKATERINA PESHEVA  December 13, 2016

Rhabdoid tumors are among the most recalcitrant childhood cancers, and scientists have long sought ways to understand what drives their resilience and makes them impervious to treatment.

Now researchers from Harvard Medical School, St. Jude Children’s Research Hospital and elsewhere have uncovered a molecular chain of events that interferes with a key mechanism that regulates cell behavior and controls tumor formation.    

Rhabdoid tumors typically start out in the kidneys, but they can also arise or migrate into the brain and other soft tissues. While rare—they account for less than 2 percent of pediatric kidney cancers—rhabdoid tumors are highly lethal with a survival rate of less than 25 percent.

The report of the multi-institutional team’s findings, published Dec. 12 in Nature Genetics, describes how the loss of a protein, SMARCB1, can disrupt the work of a regulatory mechanism, thereby fueling uncontrolled malignant cell proliferation and the continued survival of rhabdoid tumors.

The absence of SMARCB1 in rhabdoid tumor cells has been known for some time, so scientists suspected it played a role in cancer development. Yet, just how it did so remained somewhat of a puzzle.

The new findings provide the missing piece in that puzzle and reveal just how the absence of SMARCB1 unlocks a chain of events that culminates in the loss of cellular identity and profound aberrations in cell behavior.

“SMARCB1 is a key component of a protein complex known as SWI/SNF, which largely acts as a tumor suppressor. SWI/SNF works by altering the packaging of genetic material inside a cell’s nucleus. Such alterations are important because they make DNA accessible to proteins that turn on gene expression, a fundamental way to regulate cell behavior and determine cell identity.

   “Our results shed light into the long-standing mystery of rhabdoid tumor behavior,” said study co-senior author Peter Park, associate professor of biomedical Informatics at HMS. “They reveal just how  SMARCB1 becomes the central character that unleashes mischief in a twisted plot of epigenetic changes that alter cell identity and fuel cancer formation.”

The findings, the research team said, identify possible treatment targets and provide a conceptual framework for designing therapies.

In addition, the team said, the results may have relevance for other forms of cancer.

   “Mutations in the SWI/SNF complex occur in a broad range of human cancers so our findings may provide insight well beyond rhabdoid tumors,” said Charles Roberts, co-senior author and director of the Comprehensive Cancer Center at St. Jude.

     The curious case of the mutation-free tumor

Throughout the past decade, advances in cancer genome sequencing have revealed cancer cells have very high rates of genetic mutations. This mutability turns tumors into shape-shifters capable of evading drug therapies. But, curiously, rhabdoid tumors are among the most genomically stable and least mutable of cancers, harboring only a few genetic mutations, compared with the hundreds or thousands of mutations in other cancers. So what exactly makes these immutable tumors so pernicious, the researchers wondered?

Based on the study’s findings, the answer appears to lie—literally—outside of the tumor cell’s DNA and in its epigenome—the separate layer of proteins and chemical modifiers that sits atop DNA and can profoundly alter its behavior.

      Cancer’s survival kit

   The insights illuminate a critical survival mechanism that allows rhabdoid tumors to escape the body’s checks and controls.

In a series of experiments with patient-derived rhabdoid tumor tissue, the investigators showed that the absence of SMARCB1 interferes with SWI/SNF’s function.  Researchers observed the lack of SMARCB1 dramatically reduced the levels of several other proteins that make up the SWI/SNF complex, severely weakening its regulatory ability.

     Specifically, SMARCB1 deletion interfered with the SWI/SNF’s ability to bind to genetic switches called enhancers—snippets of DNA that act as genome regulators to determine which genes get turned on and which ones remain dormant.

      Some 10,000 to 20,000 enhancers are turned on in any given cell at any given time. Because all cells in an organism share the same DNA, the activity of these genetic switches is critical to determining which genes in a cell get activated to produce what proteins. In other words, enhancers play a vital role in determining the identity and behavior of a given cell.

Loss of SMARCB1, the experiments showed, led to the deactivation of many of the regular enhancers that modulate gene expression and cell behavior, while at the same time keeping another set of enhancers switched on. The researchers think it is precisely those “on” enhancers that may be critical to tumor growth and survival.

   “If something goes wrong in deciding which enhancers should be on, the cell loses its identity,” said co-investigator Burak Han Alver, a research associate in biomedical informatics at HMS who focuses on epigenetic regulation and transcription. “When that happens, in most cases, the cells will realize there is a problem and trigger self-death. But, in rare cases, errors in the enhancer landscape can lead to cancer. This is what we observed is happening in the case of rhabdoid tumor formation.”

Finding a way to shut off the remaining active enhancers, the researchers said, could turn out to be a chink in the armor of rhabdoid tumors and provide a target for treatment.

    In a final, proof-of-concept step, the scientists restored SMARCB1 inside cell lines derived from patient tumors. The tumor cell lines stopped growing, a finding that underscores the protein’s role in curbing tumor formation, the team said.

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