Uncropped gels.Lanes used for the figures presented in the manuscript are indicated with stars (*) above them. Full unedited gel for Figure 2E. Tubulin * * * * * * LCN2 * * Full unedited gels for Figure 2H.
Senescent cells are found to accumulate in aged individuals, as well as in cancer patients that receive chemotherapeutic treatment. Although originally believed to halt cancer progression due to their characteristic growth arrest, senescent cells remain metabolically active and secrete a combination of inflammatory agents, growth factors and proteases, collectively known as the senescence-associated secretory phenotype (SASP). In this review, we discuss the contribution of senescent cells to cancer progression through their ability to alter cancer cells’ properties and to generate a microenvironment that promotes tumor growth. Furthermore, recent evidence suggests that senescent cells are able resume proliferation and drive cancer relapse, pointing to the use of senolytics and SASP modulators as a potential approach to prevent tumor resurgence following treatment cessation. Thus, a better understanding of the hallmarks of senescence and the impact of the SASP will allow the development of improved targeted therapeutic strategies to leverage vulnerabilities associated with this cellular state.
Summary
Methylation of histone 3 at lysine 9 (H3K9) constitutes a roadblock for cellular reprogramming. Interference with methyltransferases or activation of demethylases by the cofactor ascorbic acid (AA) facilitates the derivation of induced pluripotent stem cells (iPSCs), but possible interactions between specific methyltransferases and AA treatment remain insufficiently explored. We show that chemical inhibition of the methyltransferases EHMT1 and EHMT2 counteracts iPSC formation in an enhanced reprogramming system in the presence of AA, an effect that is dependent on EHMT1. EHMT inhibition during enhanced reprogramming is associated with rapid loss of H3K9 dimethylation, inefficient downregulation of somatic genes, and failed mesenchymal-to-epithelial transition. Furthermore, transient EHMT inhibition during reprogramming yields iPSCs that fail to efficiently give rise to viable mice upon blastocyst injection. Our observations establish novel functions of H3K9 methyltransferases and suggest that a functional balance between AA-stimulated enzymes and EHMTs supports efficient and less error-prone iPSC reprogramming to pluripotency.
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.
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