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Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression

Oncogene volume 41, pages 4361–4370 (2022)Cite this article

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Abstract

The acquisition of novel detrimental cellular properties following exposure to cytotoxic drugs leads to aggressive and metastatic tumors that often translates into an incurable disease. While the bulk of the primary tumor is eliminated upon exposure to chemotherapeutic treatment, residual cancer cells and non-transformed cells within the host can engage a stable cell cycle exit program named senescence. Senescent cells secrete a distinct set of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Upon exposure to the SASP, cancer cells undergo cellular plasticity resulting in increased proliferation, migration and epithelial-to-mesenchymal transition. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that breast cancer cells exposed to the SASP strongly upregulate Lipocalin-2 (LCN2). Furthermore, we demonstrate that LCN2 is critical for SASP-induced increased migration in breast cancer cells, and its inactivation potentiates the response to chemotherapeutic treatment in mouse models of breast cancer. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, and correlates with worse overall survival. These findings provide the foundation for targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive tumors following chemotherapy.

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Fig. 1: The IL-1-dependent SASP promotes cellular plasticity in breast cancer cells.
Fig. 2: Exposure to the SASP induces expression of LCN2 in breast cancer cells.
Fig. 3: LCN2 upregulation is required for SASP-induced cell plasticity.
Fig. 4: SASP-induced LCN2 expression promotes breast cancer progression in vivo.
Fig. 5: SASP-induced LCN2 protects breast cancer cells from genotoxic stress.
Fig. 6: LCN2 expression is induced following chemotherapy and is a poor prognostic factor in breast cancer patients.

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Data availability

Raw transcriptomic data were deposited at GEO and are available under accession numbers GSE198661 and GSE198685. Additional data that support the findings of this study are available in figshare with the identifier: https://doi.org/10.6084/m9.figshare.20017631.

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Acknowledgements

The authors sincerely thank all members of the David lab for helpful discussions during the preparation of this manuscript. We wish to acknowledge the NYU Genome Technology Center for help with RNA sequencing (RNA-seq). We thank Dr. Richard Possemato (NYU School of Medicine), Dr. Eva Hernando (NYU School of Medicine), Dr. Thales Papagiannakopoulos (NYU School of Medicine), Dr. Benjamin Neel (NYU School of Medicine), and Dr. Judith Campisi (Buck Institute for Research on Aging) as well as members of their labs for the generous gift or reagents and plasmids and for helpful discussions. This work was funded by NIH/NCI (CA246416) [GD], NYS DoH (C36617GG) [GD] and the NYSTEM Institutional Training Grant (C322560GG) [JMV].

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  1. These authors contributed equally: Jorge Morales-Valencia, Lena Lau.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY, 10016, USA

    Jorge Morales-Valencia, Lena Lau, Teresa Martí-Nin & Gregory David

  2. NYU Langone Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA

    Jorge Morales-Valencia & Gregory David

  3. Department of Pathology, New York University School of Medicine, NYU Langone Health, New York, NY, 10016, USA

    Ugur Ozerdem

  4. Department of Urology, New York University School of Medicine, NYU Langone Health, New York, NY, 10016, USA

    Gregory David

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Contributions

The authors confirm contribution to the paper as follows: LL initiated the study under supervision of GD and contributed to Figs. 1 and 2 of the manuscript. JMV designed, performed, and analyzed data from the experiments presented in this manuscript. TMN contributed to sample preparation. UD provided patient samples and analyzed the data. GD designed the study and supervised the research. JMV and GD wrote the manuscript. All authors reviewed the results and approved final version of the manuscript.

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Correspondence to Gregory David.

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Morales-Valencia, J., Lau, L., Martí-Nin, T. et al. Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression. Oncogene 41, 4361–4370 (2022). https://doi.org/10.1038/s41388-022-02433-4

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