Tosoni Daniela, Pambianco Sarah, Ekalle Soppo Blanche, Zecchini Silvia, Bertalot Giovanni, Pruneri Giancarlo, Viale Giuseppe, Di Fiore Pier Paolo, Pece Salvatore
Istituto Europeo di Oncologia, Milan, Italy.
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
EMBO Mol Med. 2017 May;9(5):655-671. doi: 10.15252/emmm.201606940.
The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb-knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb-deficient human BCs could represent a novel anti-CSC therapy. Here, using patient-derived xenografts, we show that expansion of the CSC pool, due to altered self-renewing divisions, is also a feature of Numb-deficient human BCs. In these cancers, using the inhibitor Nutlin-3 to restore p53, we corrected the defective self-renewal properties of Numb-deficient CSCs and inhibited CSC expansion, with a marked effect on tumorigenicity and metastasis. Remarkably, a regimen combining Nutlin-3 and chemotherapy induced persistent tumor growth inhibition, or even regression, and prevented CSC-driven tumor relapse after removal of chemotherapy. Our data provide a pre-clinical proof-of-concept that targeting Numb/p53 results in a specific anti-CSC therapy in human BCs.
细胞命运决定因子Numb在人类乳腺癌（BC）中经常下调，导致p53失活和疾病进展侵袭性增强。在小鼠乳腺中，Numb/p53下调会导致异常的组织形态发生、干细胞区室的扩张以及癌症干细胞（CSC）的出现。引人注目的是，Numb基因敲除小鼠模型中的CSC表型可通过恢复Numb/p53来逆转。因此，针对Numb缺陷型人类BC中Numb/p53功能障碍可能代表一种新型的抗CSC疗法。在此，我们使用患者来源的异种移植模型表明，由于自我更新分裂改变导致的CSC池扩张也是Numb缺陷型人类BC的一个特征。在这些癌症中，我们使用抑制剂Nutlin-3恢复p53，纠正了Numb缺陷型CSC的自我更新缺陷特性并抑制了CSC扩张，对肿瘤发生和转移有显著影响。值得注意的是，联合使用Nutlin-3和化疗的方案可诱导持续的肿瘤生长抑制甚至肿瘤消退，并防止化疗撤除后CSC驱动的肿瘤复发。我们的数据提供了一个临床前概念验证，即针对Numb/p53可在人类BC中产生一种特异性的抗CSC疗法。
