Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Rhodes College, Memphis, TN, 38112, USA.
Nat Commun. 2021 Sep 17;12(1):5520. doi: 10.1038/s41467-021-25829-4.
PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.
PTEN 启动子超甲基化几乎普遍存在，并且在约 25%的融合阴性横纹肌肉瘤（FN-RMS）中发生 PTEN 拷贝数丢失。在这里，我们在 FN-RMS 的小鼠模型中显示 Pten 缺失导致分化程度更低的肿瘤更类似于人类胚胎 RMS。PTEN 缺失激活了 PI3K 途径，但没有增加 mTOR 活性。在野生型肿瘤中，PTEN 表达在核内，这表明核内 PTEN 功能的丧失可能解释了这些表型。Pten 缺失的肿瘤中表达了在神经和骨骼肌发育中重要的转录因子，包括 Dbx1 和 Pax7。Pax7 缺失完全挽救了 Pten 缺失的影响。引人注目的是，这些 Pten;Pax7 缺失的肿瘤不再是 FN-RMS，而是显示出类似于平滑肌肉瘤的平滑肌分化。这些数据强调了 FN-RMS 中 Pten 缺失如何与 PAX7 谱系特异性转录输出相关联，这种输出导致对转录因子 PAX7 的依赖性或合成必需性，以维持肿瘤特性。
