梅林(蛋白质)
神经鞘瘤
2型神经纤维瘤病
生物
遗传异质性
癌症研究
突变体
神经纤维瘤病
细胞生物学
抑制器
遗传学
病理
基因
医学
表型
作者
Christine Chiasson-MacKenzie,Jérémie Vitte,Ching-Hui Liu,Emily A. Wright,Elizabeth A. Flynn,Shannon L. Stott,Marco Giovannini,Andrea I. McClatchey
标识
DOI:10.1038/s41467-023-37226-0
摘要
Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2-/- Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma and exploited the synchronous development of lesions in a mouse model to establish a quantitative pipeline for studying how schwannoma heterogeneity evolves. Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers.
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