Lipocalin 2 upregulation mediates the detrimental effects of therapy-induced senescence in breast cancer cells

Abstract

Cancer therapy has improved patient outcomes markedly over the last two decades. However, cancer treatments have been shown to induce senescence in different cell types. Senescent cells secrete a distinct set of factors, collectively termed the senescence-associated secretory phenotype (SASP), which has been postulated to carry both pro- and antitumorigenic properties. Pro-tumorigenic functions of the SASP include enhancement of cancer cell proliferation, induction of epithelial-to-mesenchymal transition and increased migration. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that exposure to the SASP induces loss of epithelial markers and enhanced migration in breast cancer cells, along with limited transcriptional changes. In particular, we find that Lipocalin 2 (LCN2) is strongly upregulated upon exposure to the SASP, and its inactivation impairs SASP-induced migration. Moreover, we show that in presence of senescence-inducing stimuli, LCN2 promotes breast cancer tumor growth in vivo. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, which correlates with worse overall survival. These findings provide insight into the potential of targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive relapsed breast tumors following chemotherapy.

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

“…On day 14, all cell lines display high senescence scores suggesting that they all engage in a related transcriptional programme. Of note, all samples with a high senescence score are also enriched in EMT which is coherent with previous observations of EMT in different epithelial cell types after induction of senescence (fibroblasts, colorectal and lung cancer) [19,20,21].…”

“…Interestingly, all samples with a high senescence score are also enriched in EMT. EMT has been observed after induction of senescence in different epithelial cell types (fibroblasts, colorectal and lung cancer) [21, 22, 23]. Therapy-induced senescence and EMT share common transcription factors with opposite effects on both processes (Supp Fig.…”