Disrupting cellular memory to overcome drug resistance

Area of Science:

• Cellular biology
• Molecular biology
• Cancer research

Background:

• Gene expression memory, the persistence of gene expression states in single cells, influences cell fate.
• State switching, or loss of gene expression memory, can occur without genetic alterations.
• Current methods for identifying regulators of gene expression memory and tracking state switching are limited.

Purpose of the Study:

• To develop a lineage tracing-based technique for quantifying gene expression memory and identifying state-switching cells.
• To investigate gene expression dynamics in melanoma cells and their link to targeted therapy resistance.
• To identify modulators of gene expression memory and cell fate in melanoma.

Main Methods:

• Development of a novel lineage tracing technique to measure gene expression memory.
• Application of the technique to melanoma cells to quantify memory and identify state-switching dynamics.
• Analysis of gene expression fluctuations predictive of resistance to targeted therapy.

Main Results:

• Quantification of long-lived gene expression fluctuations in untreated melanoma cells.
• Identification of the PI3K and TGF-β pathways as critical modulators of gene expression state switching.
• Demonstration that a pretreatment model involving a PI3K inhibitor followed by targeted therapy reduces therapy resistance.

Conclusions:

• The developed lineage tracing method effectively quantifies gene expression memory and identifies state-switching cells.
• PI3K and TGF-β pathways play significant roles in regulating gene expression memory and cell fate in melanoma.
• A novel pretreatment strategy combining PI3K inhibition with targeted therapy shows promise in overcoming melanoma resistance.