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Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Abstract

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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Fig. 1: Nuclear size and stiffness vary widely across breast cancer cell lines and correspond to lamin A/C levels.
Fig. 2: Decreased A-type lamin levels result in the enhanced nuclear deformability of invasive breast cancer cells.
Fig. 3: Decreased Lamin A levels facilitate migration through confined spaces.
Fig. 4: Breast cancer cells with increased metastatic capacity have reduced lamin A expression.
Fig. 5: Increasing lamin A in breast cancer cells alters expression of proteins involved in cell metabolism, extracellular remodeling, adhesion, and cytoskeleton dynamics.
Fig. 6: Lamin A levels modulate breast cancer cell morphology and proliferation.
Fig. 7: Decreased A-type lamin levels are associated with increased proliferation and Akt signaling in human breast tumors.
Fig. 8: Decreased lamin A levels are associated with worse prognosis in breast cancer.

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Acknowledgements

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.

Funding

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).

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ESB and JL conceptualized and designed the experiments; JL supervised the research; ESB, PS, NZS, AAV, JLPM, and ALM performed experiments and analyzed data; DK and MS performed the SILAC proteomic analysis; PI, JJE, PMD, JNL, and VMW contributed to the development of resources, including constructs, cell lines, assays, and/or image analysis methods; PNS and LV contributed human breast tumor tissue samples and analysis; EB and JL wrote the paper; all authors contributed to the editing of the paper; and JL and MBS acquired funding.

Corresponding author

Correspondence to Jan Lammerding.

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Competing interests

JL has provided paid consulting services for BridgeBio for the role of lamins in unrelated projects.

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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

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