AP-1 mediates cellular adaptation and memory formation

Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that cancer cells can form and maintain cellular memories when becoming drug resistant, exhibiting characteristics of cellular learning that are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that cells can adapt during this time of stress. The application of therapy itself results in the encoding of transient gene expression into cellular memory and that this encoding occurs for both transiently induced and probabilistically arising expression. Chromatin accessibility shows concomitant persistence. A two-color AP-1 reporter system shows that these memories are encoded in cis, constituting an example of activating cis epigenetics. Our findings establish the formation and maintenance of cellular memories as a critical aspect of gene regulation during the development of therapy resistance.