Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.
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We thank Prof. Peter Friedl for the 4T1 progression series cell lines. This work was performed in part at the Cornell NanoScale Science & Technology Facility, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (Grant NNCI-2025233). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
This work was supported by funding from the National Institutes of Health (R01 HL082792, R01 GM137605, U54 CA210184, and U54 CA193461 to JL, R35 GM141159 and R01 GM123018 to MBS), the Department of Defense Breast Cancer Research Program (Breakthrough Award BC150580 to JL), and the National Science Foundation (CAREER Award CBET-1254846 to JL and Graduate Research Fellowship DGE-1144153 to ALM). This work was performed in part at the Cornell NanoScale Science & Technology Facility (CNF), a member of the National Nanotechnology Coordinated Infrastructure NNCI), which is supported by the National Science Foundation (Grant NNCI-2025233).
JL has provided paid consulting services for BridgeBio for the role of lamins in unrelated projects.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Bell, E.S., Shah, P., Zuela-Sopilniak, N. et al. Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer. Oncogene 41, 4211–4230 (2022). https://doi.org/10.1038/s41388-022-02420-9