胶质母细胞瘤（GB）是最常见和致命的原发性恶性脑肿瘤，目前仍缺乏有效的治疗方法。 GB干细胞具有肿瘤启动和自我更新能力，是GB恶性肿瘤的主要原因，是治疗的重要靶点。 TP73 基因在 GB 中高度表达，产生 TAp73 亚型，这是一种调节神经干细胞生物学的多效性蛋白质；然而，它在癌症中的作用一直备受争议。我们灭活了人类 GB 干细胞中的 TP73，并发现 TAp73 是其干性潜力所必需的，作为转录干性特征的调节因子，强调 TAp73 作为可能的治疗靶点。作为概念证明，我们发现了一种具有 TAp73 抑制能力的新型天然化合物，它对 GB 干细胞非常有效。该治疗降低了 GB 干细胞的侵袭能力和干细胞特征，至少部分是由于 TAp73 抑制所致。我们的数据与一种新的范式一致，其中劫持 p73 调节的神经发育程序（包括神经干性）可能维持肿瘤进展，指出 TAp73 作为 GB 的一种治疗策略。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Glioblastoma (GB) is the most common and fatal type of primary malignant brain tumor for which effective therapeutics are still lacking. GB stem cells, with tumor-initiating and self-renewal capacity, are mostly responsible for GB malignancy, representing a crucial target for therapies. The TP73 gene, which is highly expressed in GB, gives rise to the TAp73 isoform, a pleiotropic protein that regulates neural stem cell biology; however, its role in cancer has been highly controversial. We inactivated TP73 in human GB stem cells and revealed that TAp73 is required for their stemness potential, acting as a regulator of the transcriptional stemness signatures, highlighting TAp73 as a possible therapeutic target. As proof of concept, we identified a novel natural compound with TAp73-inhibitory capacity, which was highly effective against GB stem cells. The treatment reduced GB stem cell-invasion capacity and stem features, at least in part by TAp73 repression. Our data are consistent with a novel paradigm in which hijacking of p73-regulated neurodevelopmental programs, including neural stemness, might sustain tumor progression, pointing out TAp73 as a therapeutic strategy for GB.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.