Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, 79104, Germany.
Faculty of Biology, University of Freiburg, Freiburg, 79104, Germany.
Nat Commun. 2020 Oct 12;11(1):5133. doi: 10.1038/s41467-020-18935-2.
Cathepsin D (CTSD) is a lysosomal protease and a marker of poor prognosis in breast cancer. However, the cells responsible for this association and the function of CTSD in cancer are still incompletely understood. By using a conditional CTSD knockout mouse crossed to the transgenic MMTV-PyMT breast cancer model we demonstrate that CTSD deficiency in the mammary epithelium, but not in myeloid cells, blocked tumor development in a cell-autonomous manner. We show that lack of CTSD impaired mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling and induced reversible cellular quiescence. In line, CTSD-deficient tumors started to grow with a two-month delay and quiescent Ctsd tumor cells re-started proliferation upon long-term culture. This was accompanied by rewiring of oncogenic gene expression and signaling pathways, while mTORC1 signaling remained permanently disabled in CTSD-deficient cells. Together, these studies reveal a tumor cell-autonomous effect of CTSD deficiency, and establish a pivotal role of this protease in the cellular response to oncogenic stimuli.
组织蛋白酶 D（CTSD）是一种溶酶体蛋白酶，是乳腺癌预后不良的标志物。然而，负责这种关联的细胞以及 CTSD 在癌症中的功能仍不完全清楚。通过使用条件性 CTSD 敲除小鼠与转基因 MMTV-PyMT 乳腺癌模型杂交，我们证明乳腺上皮细胞中的 CTSD 缺乏而非髓细胞中的 CTSD 缺乏以细胞自主的方式阻断了肿瘤的发展。我们表明缺乏 CTSD 会损害雷帕霉素靶蛋白复合物 1（mTORC1）信号通路，并诱导可逆的细胞静止。与此一致，缺乏 CTSD 的肿瘤开始生长的时间延迟了两个月，并且在长期培养后静止的 Ctsd 肿瘤细胞重新开始增殖。这伴随着致癌基因表达和信号通路的重新布线，而 mTORC1 信号通路在 CTSD 缺乏的细胞中仍然永久失活。总之，这些研究揭示了 CTSD 缺乏的肿瘤细胞自主效应，并确立了这种蛋白酶在细胞对致癌刺激的反应中的关键作用。
