Institut Curie - Recherche, Laboratoire 110, Centre Universitaire, Orsay Cedex 91405, France; INSERM U1021, Centre Universitaire, Orsay 91405, France; CNRS UMR 3347, Centre Universitaire, Orsay 91405, France; Université Paris Sud-11, 91405 Orsay, France; PSL Research University, Paris, France.
Baylor College of Medicine, Department of Molecular and Human Genetics, 1 Baylor Plaza, Houston, TX 77030, USA.
Cancer Cell. 2018 Mar 12;33(3):435-449.e6. doi: 10.1016/j.ccell.2018.02.006.
Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.
癌细胞通常表达与其起源组织无关的分化程序，尽管这些异常表型对恶性肿瘤的贡献还不太清楚。成神经管细胞瘤是一种起源于小脑的恶性小儿脑肿瘤，其中一个侵袭性亚组表达正常在视网膜中表达的光感受器分化程序。我们确定了两个光感受器特异性转录因子，NRL 和 CRX，是该程序的主要调节因子，并且是该亚组肿瘤维持所必需的。除了光感受器谱系基因外，我们还将 BCL-XL 鉴定为 NRL 的关键转录靶标，并提供证据证实抗 BCL 治疗是某些 MB 患者的合理治疗机会。我们的研究结果强调了研究癌症中异常分化程序及其作为选择性治疗弱点的潜力的实用性。
