The diapause-like quiescent state of cancer cells presents a unique epigenetic profile and specific vulnerabilities
[eng] Anti-cancer therapies are based on the infliction of damage or stress to cancer cells, with the aim of triggering cell death. In practice, a fraction of cancer cells often evades cell death and enters a state of cell cycle arrest. Cell death evasion can lead to the entry of the cells into the...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/212625 |
| Acceso en línea: | https://hdl.handle.net/2445/212625 http://hdl.handle.net/10803/691394 |
| Access Level: | acceso abierto |
| Palabra clave: | Epigenètica Cèl·lules canceroses Patologia cel·lular Epigenetics Cancer cells Cellular pathology |
| Sumario: | [eng] Anti-cancer therapies are based on the infliction of damage or stress to cancer cells, with the aim of triggering cell death. In practice, a fraction of cancer cells often evades cell death and enters a state of cell cycle arrest. Cell death evasion can lead to the entry of the cells into the state of therapy-induce senescence (TIS) or into a state of drug-tolerant persistency (DTP). Recent work has unveiled similarities between DTP and embryonic diapause, a reversible process of cell cycle arrest triggered by unfavorable conditions during embryonic development. Consequently, drug-tolerant persister cells are also referred to as "diapause-like cancer cells" (DLCCs). While TIS has been extensively studied, less is known about DLCCs. In this doctoral work, we characterize a new in vitro model of DLCCs that relies on dual mTOR/PI3K inhibition. Using this system, we perform a comprehensive characterization of the DLCC phenotype, specifically in comparison to TIS. We analyze classical senescence features, such as the senescence-associated secretory phenotype (SASP), the lysosomal mass increase, ROS accumulation, etc., in order to uncover shared and differential traits of DLCCs. Moreover, we unveil a possible common vulnerability of TIS and DLCCs, namely, their sensitivity to BCL-XL inhibition. We leverage the resemblance of DLCCs to embryonic diapause in a genome-wide CRISPR/Cas9 screen, through which we unravel a pivotal role for the one carbon (1C) metabolism in the survival of DLCCs. Among its many cellular functions, 1C metabolism provides methyl groups for histone and DNA methylation. Accordingly, we report increased levels of H3K9 trimethylation and H4K20 trimethylation in DLCCs compared to proliferating cancer cells and a differential enrichment of H4K20me3 in DLCCs and TIS, specifically at promoter regions of genes that are differentially regulated between the two states. Mechanistically, we show that this may be a driver of the distinct inflammatory profiles of these alternative cell fates. While cells undergoing TIS exhibit decreased H4K20me3 along promoters of interferon (IFN)- and senescence-associated secretory phenotype (SASP)-related genes and transcriptional upregulation, DLCCs gain or retain H4K20me3 at these same loci, associated with the absence of gene expression. In conclusion, DLCCs exhibit a distinct phenotype with both shared and distinct traits from TIS. We define novel vulnerabilities to target DTP/DLCC cells and we provide insight into the epigenetic mechanisms underlying the low inflammatory activity of this cellular state. |
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