Persistence and/or Senescence: Not So Lasting at Last?

Area of Science:

• Cancer Biology
• Epigenetics
• Cellular Senescence

Background:

• Therapy-resistant cancer cells can persist, leading to aggressive relapses.
• These drug-tolerant persisters are often characterized as senescent or senescence-like.
• Understanding persister cell biology is crucial for overcoming treatment failure.

Purpose of the Study:

• To model drug-tolerant persistence using embryonic diapause-like arrest (DLA) in cancer cells.
• To compare DLA-induced persistence with therapy-induced senescence.
• To identify epigenetic vulnerabilities of DLA-like persister cells.

Main Methods:

• Utilized mTOR/PI3K inhibitor to induce DLA in lung cancer and melanoma cells.
• Compared DLA phenotype with therapy-induced senescence.
• Performed CRISPR dropout screens to identify genetic dependencies.
• Investigated the role of one-carbon metabolism and H4K20 methylation.

Main Results:

• DLA cells showed some, but not all, features of senescence, notably lacking the inflammatory senescence-associated secretory phenotype (SASP).
• CRISPR screens identified one-carbon metabolism and H4K20me3 as critical for DLA-like persisters.
• H4K20me3 selectively repressed SASP-related IFN response genes in DLA cells.
• Inhibition of KMT5B/C methyltransferases was toxic to DLA cells by derepressing inflammatory programs.

Conclusions:

• DLA serves as a distinct model for studying drug-tolerant cancer persistence.
• Epigenetic regulation, specifically H4K20 methylation, plays a key role in DLA-like persister cell characteristics.
• Targeting one-carbon metabolism and H4K20-active methyltransferases presents potential therapeutic strategies against persister cells.
• The study highlights challenges in modeling persister cells using cultured cell lines.