Persistence and/or senescence: not so lasting at last?

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Item Type:	Editorial
Title:	Persistence and/or senescence: not so lasting at last?
Creators Name:	Schmitt, C.A.
Abstract:	Therapy-exposed surviving cancer cells may have encountered profound epigenetic remodeling that renders these drug-tolerant persisters candidate drivers of particularly aggressive relapses. Typically presenting as slow-to-nongrowing cells, persisters are senescent or senescence-like cells. In this issue of Cancer Research, Ramponi and colleagues study mTOR/PI3K inhibitor–induced embryonic diapause–like arrest (DLA) as a model of persistence in lung cancer and melanoma cells and compare this persister condition with therapy-induced senescence in the same cells. The DLA phenotype recapitulated some but not all features attributed to senescent cells, lacking, for instance, an inflammatory secretome otherwise known as the senescence-associated secretory phenotype. A CRISPR dropout screen pointed to methyl group–providing one-carbon metabolism and further to H4K20me3-mediated repression of senescence-associated secretory phenotype–related IFN response genes selectively in DLA-like persister cells. Conversely, inhibition of H4K20-active KMT5B/C methyltransferases derepressed inflammatory programs and was toxic in DLA cells. These findings not only suggest exploitable vulnerabilities of DLA-like persister cells but also unveil general technical and conceptual challenges of cultured multipassage cell line–based persister studies. Collectively, the approach chosen and insights obtained will stimulate a productive scientific debate on senescence-like features and their reversibility across drug-tolerant persister cells.
Keywords:	Cellular Senescence, TOR Serine-Threonine Kinases, Animals
Source:	Cancer Research
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Volume:	85
Number:	1
Page Range:	7-9
Date:	2 January 2025
Official Publication:	https://doi.org/10.1158/0008-5472.CAN-24-3744
PubMed:	View item in PubMed

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