Remy David, Antoine-Bally Sandra, de Toqueville Sophie, Jolly Célia, Macé Anne-Sophie, Champenois Gabriel, Nemati Fariba, Brito Isabel, Raynal Virginie, Priya Amulya, Berlioz Adèle, Dahmani Ahmed, Nicolas André, Meseure Didier, Marangoni Elisabetta, Chavrier Philippe
Institut Curie, CNRS UMR 144, PSL University, 75005 Paris, France.
Institut Curie, CNRS UMR 144, PSL University, 75005 Paris, France.
Dev Cell. 2025 Apr 7;60(7):1018-1035.e8. doi: 10.1016/j.devcel.2024.12.005. Epub 2024 Dec 26.
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently hyperactivated in triple-negative breast cancers (TNBCs) associated with poor prognosis and is a therapeutic target in breast cancer management. Here, we describe the effects of repression of mTOR-containing complex 1 (mTORC1) through knockdown of several key mTORC1 components or with mTOR inhibitors used in cancer therapy. mTORC1 repression results in an ∼10-fold increase in extracellular matrix proteolytic degradation. Repression in several TNBC models, including in patient-derived xenografts (PDXs), induces nuclear translocation of transcription factor EB (TFEB), which drives a transcriptional program that controls endolysosome function and exocytosis. This response triggers a surge in endolysosomal recycling and the surface exposure of membrane type 1 matrix metalloproteinase (MT1-MMP) associated with invadopodia hyperfunctionality. Furthermore, repression of mTORC1 results in a basal-like breast cancer cell phenotype and disruption of ductal carcinoma in situ (DCIS)-like organization in a tumor xenograft model. Altogether, our data call for revaluation of mTOR inhibitors in breast cancer therapy.
磷脂酰肌醇3激酶（PI3K）/AKT/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路在预后不良的三阴性乳腺癌（TNBC）中经常过度激活，是乳腺癌治疗的一个靶点。在此，我们描述了通过敲低几种关键的mTORC1组分或使用癌症治疗中使用的mTOR抑制剂来抑制含mTOR的复合物1（mTORC1）的效果。mTORC1的抑制导致细胞外基质蛋白水解降解增加约10倍。在包括患者来源异种移植瘤（PDX）在内的几种TNBC模型中的抑制作用诱导了转录因子EB（TFEB）的核转位，TFEB驱动一个控制内溶酶体功能和胞吐作用的转录程序。这种反应引发了内溶酶体再循环的激增以及与侵袭伪足功能亢进相关的膜型1基质金属蛋白酶（MT1-MMP）的表面暴露。此外，mTORC1的抑制导致基底样乳腺癌细胞表型，并在肿瘤异种移植模型中破坏原位导管癌（DCIS）样组织。总之，我们的数据呼吁重新评估mTOR抑制剂在乳腺癌治疗中的作用。
