Elkholi Islam E, Robert Amélie, Malouf Camille, Wu Joshua L, Kuasne Hellen, Drapela Stanislav, Macleod Graham, Hébert Steven, Pacis Alain, Calderon Virginie, Kleinman Claudia L, Gomes Ana P, Alvarez James V, Aguirre-Ghiso Julio A, Park Morag, Angers Stéphane, Côté Jean-François
Montreal Clinical Research Institute, Montreal, Canada.
Molecular Biology Programs, Université de Montréal, Montreal, Canada.
Cancer Res. 2025 Jun 16;85(12):2179-2198. doi: 10.1158/0008-5472.CAN-23-2654.
Halting breast cancer metastatic relapse following primary tumor removal remains challenging due to a lack of specific vulnerabilities to target during the clinical dormancy phase. To identify such vulnerabilities, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). The dormancy-prone 4T07 cells displayed a unique dependency on class III PI3K (PIK3C3). Unexpectedly, 4T07 cells exhibited higher mechanistic target of rapamycin complex 1 (mTORC1) activity than 4T1 cells due to lysosome-dependent signaling occurring at the cell periphery. Pharmacologic inhibition of PIK3C3 suppressed this phenotype in the 4T1-4T07 models as well as in human breast cancer cell lines and a breast cancer patient-derived xenograft. Furthermore, inhibiting PIK3C3 selectively reduced metastasis burden in the 4T07 model and eliminated dormant cells in a HER2-dependent murine breast cancer dormancy model. These findings suggest that PIK3C3-peripheral lysosomal signaling to mTORC1 may represent a targetable axis for preventing dormant cancer cell-initiated metastasis in patients with breast cancer.
Dormancy-prone breast cancer cells depend on the class III PI3K to mediate peripheral lysosomal positioning and mTORC1 hyperactivity, which can be targeted to blunt breast cancer metastasis.
由于在临床休眠期缺乏可靶向的特定脆弱点，在原发性肿瘤切除后阻止乳腺癌转移复发仍然具有挑战性。为了确定此类脆弱点，我们对两种具有不同休眠特性的乳腺癌细胞系进行了全基因组CRISPR筛选：4T1（短期休眠）和4T07（长期休眠）。易于进入休眠状态的4T07细胞对III类PI3K（PIK3C3）表现出独特的依赖性。出乎意料的是，由于细胞外周发生的溶酶体依赖性信号传导，4T07细胞表现出比4T1细胞更高的雷帕霉素复合物1（mTORC1）活性。PIK3C3的药理学抑制在4T1-4T07模型以及人乳腺癌细胞系和乳腺癌患者来源的异种移植中抑制了这种表型。此外，抑制PIK3C3在4T07模型中选择性降低转移负担，并在HER2依赖性小鼠乳腺癌休眠模型中消除休眠细胞。这些发现表明，PIK3C3-外周溶酶体向mTORC1的信号传导可能代表了预防乳腺癌患者中休眠癌细胞引发转移的一个可靶向轴。
易于进入休眠状态的乳腺癌细胞依赖III类PI3K来介导外周溶酶体定位和mTORC1过度活跃，这可以作为靶点来抑制乳腺癌转移。
