Towards Novel Differentiation Therapies for Neuroblastoma.

神经母细胞瘤(NB)是一种起源于神经嵴的恶性肿瘤，约占儿童肿瘤的15%。 癌症死亡。重要的是，NB起源于交感神经-肾上腺前体细胞分化失败。 此外，肿瘤的分化程度与NB的预后密切相关，因为 未分化的肿瘤预示着总体存活率较低。我们最近发现了一种新的途径， 能够限制NB的分化，而这一途径涉及组蛋白伴侣蛋白的去调节 CHAF1A(染色质组装因子-1A)。CHAF1A是一种主要的表观遗传和转录调控因子，其 最近，异常表达被认为与许多癌症的发生有关。我们发现这么高 CHAF1A的表达强烈预示着不良的NB存活率和未分化的表型。重要的是，我们展示了 CHAF1a对体内肿瘤的建立和生长是必需的，限制了NB的分化，并重新连接 独特的新陈代谢程序。因此，我们的指导性假设是，NB仍然冻结在高度未分化的 这种状态的部分原因是CHAF1A介导的分化程序和代谢重编程的抑制。 我们的工作模式是，通过阻断CHAF1A功能，我们可以驱动NB分化。的具体目标 这项提议将检验这些假说并确定：1)CHAF1a对NB抗性的贡献 分化治疗，2)CHAF1a阻断NB分化的分子机制 重新编程肿瘤代谢，以及3)CHAF1A代谢重新编程如何改变NB的发生和发展 对分化治疗的反应。我们希望揭示CHAF1A反对的分子机制 在CHAF1a驱动的肿瘤细胞中，NB分化和确定改变肿瘤代谢的基因和途径 肿瘤发生学。我们预计拟议的研究还将提供更广泛的新见解 NB分化和能量代谢的转录调控在NB进展和抗性中的作用 心理治疗。这些研究将具有重要意义，因为这些发现将导致开发新的分化疗法 注意：

Neuroblastoma (NB) is a neural crest-derived malignancy that accounts for approximately 15% of pediatric cancer deaths. Importantly, NB arises from a failure of sympathoadrenal progenitors to differentiate. Furthermore, the degree of tumor differentiation strongly correlates with NB outcome, as the most undifferentiated tumors are predictive of poor overall survival. We have recently identified a novel pathway that is capable of restricting NB differentiation, and this pathway involves de-regulation of the histone chaperone CHAF1A (chromatin assembling factor-1A). CHAF1A is a major epigenetic and transcriptional regulator and its aberrant expression has recently been linked to tumorigenesis in numerous cancers. We found that high CHAF1A expression strongly predicts poor NB survival and an undifferentiated phenotype. Importantly, we show that CHAF1A is necessary for in vivo tumor establishment and growth, restricts NB differentiation, and rewires distinct metabolic programs. Thus, our guiding hypothesis is that NB remains frozen in a highly undifferentiated state in part due to CHAF1A-mediated suppression of differentiation programs and metabolic reprogramming. Our working model is that by blocking CHAF1A functions, we can drive NB to differentiate. The specific aims of this proposal will test these hypotheses and determine: 1) the contribution of CHAF1A to NB resistance to differentiation therapy, 2) the molecular mechanisms through which CHAF1A blocks NB differentiation and reprograms tumor metabolism, and 3) how CHAF1A metabolic reprogramming alters NB tumorigenesis and response to differentiation therapy. We expect to uncover the molecular mechanisms by which CHAF1A opposes NB differentiation and to identify genes and pathways that alter tumor metabolism in CHAF1A-driven tumorigenesis. We expect that the proposed research will also more generally provide new insight into the transcriptional regulation of NB differentiation and energy metabolism in NB progression and resistance to therapy. These studies will be significant as these findings will lead to develop novel differentiation therapies for NB.