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

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.

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.

References

  1. Yedjou CG, Sims JN, Miele L, Noubissi F, Lowe L, Fonseca DD, et al. Health and racial disparity in breast cancer. Adv Exp Med Biol. 2019;1152:31–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Asaoka M, Gandhi S, Ishikawa T, Takabe K. Neoadjuvant chemotherapy for breast cancer: past, present, and future. Breast Cancer. 2020;14:1178223420980377.

    PubMed  PubMed Central  Google Scholar 

  3. Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017;7:165–76.

    CAS  PubMed  Article  Google Scholar 

  4. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192:547–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Sharpless NE, DePinho RA. Cancer: crime and punishment. Nature. 2005;436:636–7.

    CAS  PubMed  Article  Google Scholar 

  6. van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509:439–46.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21:1424–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705.

    CAS  PubMed  Article  Google Scholar 

  9. Young AR, Narita M. SASP reflects senescence. EMBO Rep. 2009;10:228–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA. 2001;98:12072–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Coppé JP, Kauser K, Campisi J, Beauséjour CM. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem. 2006;281:29568–74.

    PubMed  Article  CAS  Google Scholar 

  12. Laberge RM, Awad P, Campisi J, Desprez PY. Epithelial-mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron. 2012;5:39–44.

    CAS  PubMed  Article  Google Scholar 

  13. Xiao X, Yeoh BS, Vijay-Kumar M. Lipocalin 2: an emerging player in iron homeostasis and inflammation. Annu Rev Nutr. 2017;37:103–30.

    CAS  PubMed  Article  Google Scholar 

  14. Yang J, Moses MA. Lipocalin 2: a multifaceted modulator of human cancer. Cell Cycle. 2009;8:2347–52.

    CAS  PubMed  Article  Google Scholar 

  15. Shi H, Gu Y, Yang J, Xu L, Mi W, Yu W. Lipocalin 2 promotes lung metastasis of murine breast cancer cells. J Exp Clin Cancer Res. 2008;27:83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Birkenkamp-Demtroder K, Christensen LL, Olesen SH, Frederiksen CM, Laiho P, Aaltonen LA, et al. Gene expression in colorectal cancer. Cancer Res. 2002;62:4352–63.

    CAS  PubMed  Google Scholar 

  17. Tong Z, Kunnumakkara AB, Wang H, Matsuo Y, Diagaradjane P, Harikumar KB, et al. Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Res. 2008;68:6100–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Hu C, Yang K, Li M, Huang W, Zhang F, Wang H. Lipocalin 2: a potential therapeutic target for breast cancer metastasis. Onco Targets Ther. 2018;11:8099–106.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Lau L, Porciuncula A, Yu A, Iwakura Y, David G. Uncoupling the senescence-associated secretory phenotype from cell cycle exit via interleukin-1 inactivation unveils its protumorigenic role. Mol Cell Biol. 2019;39:e00586–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Xu H, Tian Y, Yuan X, Wu H, Liu Q, Pestell RG, et al. The role of CD44 in epithelial-mesenchymal transition and cancer development. Onco Targets Ther. 2015;8:3783–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Canino C, Mori F, Cambria A, Diamantini A, Germoni S, Alessandrini G, et al. SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene. 2012;31:3148–63.

    CAS  PubMed  Article  Google Scholar 

  23. Ortiz-Montero P, Londoño-Vallejo A, Vernot JP. Senescence-associated IL-6 and IL-8 cytokines induce a self- and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line. Cell Commun Signal. 2017;15:17.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, et al. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA. 2009;106:3913–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Villodre ES, Hu X, Larson R, Finetti P, Gomez K, Balema W, et al. Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion. Mol Oncol. 2021;15:2752–65.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Zhao D, Pan C, Sun J, Gilbert C, Drews-Elger K, Azzam DJ, et al. VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene. 2015;34:3107–19.

    CAS  PubMed  Article  Google Scholar 

  27. Poli V, Fagnocchi L, Fasciani A, Cherubini A, Mazzoleni S, Ferrillo S, et al. MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state [published correction appears in Nat Commun. 2018 Sep 20;9(1):3921]. Nat Commun. 2018;9:1024.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. Espinoza-Sánchez NA, Enciso J, Pelayo R, Fuentes-Pananá EM. An NFκB-dependent mechanism of tumor cell plasticity and lateral transmission of aggressive features. Oncotarget. 2018;9:26679–26700.

    PubMed  PubMed Central  Article  Google Scholar 

  29. Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007;67:1979–87.

    CAS  PubMed  Article  Google Scholar 

  30. Li QQ, Xu JD, Wang WJ, Cao XX, Chen Q, Tang F, et al. Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res. 2009;15:2657–65.

    CAS  PubMed  Article  Google Scholar 

  31. Saxena M, Stephens MA, Pathak H, Rangarajan A. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis. 2011;2:e179.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.

    PubMed  Article  CAS  Google Scholar 

  33. Zhang N, Ji J, Zhou D, Liu X, Zhang X, Liu Y, et al. The Interaction of the senescent and adjacent breast cancer cells promotes the metastasis of heterogeneous breast cancer cells through notch signaling. Int J Mol Sci. 2021;22:849.

    CAS  PubMed Central  Article  Google Scholar 

  34. Ewald JA, Desotelle JA, Wilding G, Jarrard DF. Therapy-induced senescence in cancer. J Natl Cancer Inst. 2010;102:1536–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Milanovic M, Fan DNY, Belenki D, Däbritz JHM, Zhao Z, Yu Y, et al. Senescence-associated reprogramming promotes cancer stemness. Nature. 2018;553:96–100.

    CAS  PubMed  Article  Google Scholar 

  36. Duy C, Li M, Teater M, Meydan C, Garrett-Bakelman FE, Lee TC, et al. Chemotherapy Induces senescence-like resilient cells capable of initiating AML recurrence. Cancer Discov. 2021;11:1542–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Karabicici M, Alptekin S, Fırtına Karagonlar Z, Erdal E. Doxorubicin-induced senescence promotes stemness and tumorigenicity in EpCAM-/CD133- nonstem cell population in hepatocellular carcinoma cell line, HuH-7. Mol Oncol. 2021;15:2185–202.

    PubMed  PubMed Central  Article  Google Scholar 

  38. Leng X, Ding T, Lin H, Wang Y, Hu L, Hu J, et al. Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. Cancer Res. 2009;69:8579–84.

    CAS  PubMed  Article  Google Scholar 

  39. Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell. 2003;113:207–19.

    CAS  PubMed  Article  Google Scholar 

  40. Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K, et al. Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep. 2016;6:21903.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Chi Y, Remsik J, Kiseliovas V, Derderian C, Sener U, Alghader M, et al. Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis. Science. 2020;369:276–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Jung M, Mertens C, Tomat E, Brüne B. Iron as a central player and promising target in cancer progression. Int J Mol Sci. 2019;20:273.

    PubMed Central  Article  CAS  Google Scholar 

  43. Pinnix ZK, Miller LD, Wang W, D’Agostino R Jr, Kute T, Willingham MC, et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med. 2010;2:43ra56.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. La Manna G, Ghinatti G, Tazzari PL, Alviano F, Ricci F, Capelli I, et al. Neutrophil gelatinase-associated lipocalin increases HLA-G(+)/FoxP3(+) T-regulatory cell population in an in vitro model of PBMC. PLoS ONE. 2014;9:e89497.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 2016;7:11479.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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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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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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