Cycling cancer persister cells arise from lineages with distinct programs

Area of Science:

• Cancer Biology
• Genetics
• Metabolism

Background:

• Non-genetic mechanisms are increasingly recognized as key factors in cancer therapy failure.
• Cancer cells can enter a drug-tolerant persister state, with a subset maintaining proliferation under continuous drug exposure.
• The mechanisms enabling proliferative capacity in drug-exposed persister cells remain largely unknown.

Purpose of the Study:

• To investigate the non-genetic mechanisms underlying the proliferative capacity of cancer persister cells.
• To identify distinct lineages and transcriptional/metabolic programs associated with cycling persisters.
• To explore therapeutic vulnerabilities in drug-tolerant persister populations.

Main Methods:

• Development of the Watermelon lentiviral barcoding system for simultaneous clonal tracing and state monitoring.
• Analysis of clonal origin, proliferation, and transcriptional states of persister cells.
• Investigation of the role of oxidative stress and metabolic reprogramming in persister cell cycling.

Main Results:

• Cycling and non-cycling persisters originate from distinct cell lineages with unique transcriptional and metabolic profiles.
• Upregulation of antioxidant programs and fatty acid oxidation are linked to persister proliferative capacity across cancer types.
• Interfering with oxidative stress or metabolic reprogramming impacts the proportion of cycling persisters.
• Persister cell programs are observed in minimal residual disease in human tumors treated with targeted therapies.

Conclusions:

• The Watermelon system effectively identifies rare, proliferative persister lineages under drug pressure.
• Metabolic reprogramming and antioxidant defenses are critical for cancer persister cell proliferation.
• Targeting these identified vulnerabilities may offer strategies to prevent cancer recurrence and disease progression.