Senescence-Associated Chromatin Remodeling Promotes Cancer Stemness

Chemotherapy and radiation promote senescence in tumor cells, and therapy-induced senescence (TIS) may enhance the efficacy of cancer therapy. However, several critical mediators of senescence—such as p53, p16^INK4a, and trimethylation of lysine 9 at histone 3 (H3K9me3)—are also associated with the acquisition of a stem-cell phenotype. Given that cancer stem cells (CSC) have been shown to promote therapeutic resistance and relapse, Milanovic and colleagues evaluated BCL2-overexpressing Eμ-Myc lymphoma, an established transgenic mouse model of therapy-induced senescence, and p53-regulatable leukemias to determine whether TIS is accompanied by cancer stemness. Unlike untreated lymphomas, TIS lymphomas were enriched for the expression of stemness genes, canonical WNT signaling, and increased ALDH and ABC transporter activities, the latter two of which have been shown to promote drug resistance in CSCs. Similarly, samples from patients with leukemia and several solid tumor types that exhibited senescence were enriched for stemness genes, and TIS-capable human cancer cell lines exhibited increased nuclear CTNNB1 expression after treatment. In a conditionally senescent model of BCL2-protected lymphomas where cotreatment of tamoxifen and adriamycin is necessary for senescence and increased expression of stemness-related genes, withdrawal of both drugs resulted in the resumption of proliferation after the inactivation of senescence-essential genes or the loss of H3K9me3. Further, previously senescent lymphomas exhibited increased H3K9me3 loss–dependent WNT signaling and expression of stemness genes, colony formation, and tumor-initiating capacity compared to never-senescent lymphomas. Pharmacologic and genetic WNT pathway knockdown extended the survival of mice implanted with previously senescent lymphomas compared to those with never-senescent lymphomas. Relapsed murine TIS lymphoma and human diffuse large B-cell lymphoma exhibited increased frequencies of Ctnnb1-positive cells compared to matched pretreatment tumors. TIS induction in the non-CSC population of murine leukemia cells driven by Kras^G12D and temporary Trp53 activation resulted in the transcriptional reprogramming of non-CSCs to CSCs. These results elucidate the mechanism underlying senescence-associated stemness and suggest potential therapeutic approaches.

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

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