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De Novo Generation of Somatic Stem Cells by YAP/TAZ
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AP-1 Mediates Cellular Adaptation and Memory Formation During Therapy Resistance
Jingxin Li1, Pavithran T Ravindran2, Aoife O'Farrell3
1Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Biorxiv : the Preprint Server for Biology
|August 2, 2024
Summary
Melanoma cells develop therapy resistance through cellular memory, a form of learning dependent on the transcription factor AP-1. This memory, encoded epigenetically, allows cells to adapt and survive treatments.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Cellular responses are traditionally viewed as genetically programmed.
- Therapy resistance in cancer is a significant clinical challenge.
Purpose of the Study:
- To investigate the role of cellular memory in the development of therapy resistance in melanoma.
- To identify the molecular mechanisms underlying therapy-induced cellular memory.
Main Methods:
- Utilized melanoma cell models exposed to varying therapy doses.
- Employed a two-color AP-1 reporter system.
- Analyzed gene expression and chromatin accessibility changes.
Main Results:
- Melanoma cells acquired resistance to high-dose therapy after low-dose exposure, indicating non-selective adaptation.
- Therapy induced transient gene expression, which was encoded into persistent cellular memory.
- Cellular memory formation was dependent on the transcription factor AP-1 and involved cis-encoded epigenetic changes.
- Chromatin accessibility demonstrated persistent changes correlating with memory formation.
Conclusions:
- Cellular memory formation is a critical mechanism in developing therapy resistance.
- This process involves transcription factor AP-1 and activating cis epigenetics.
- Cellular memory represents a form of cellular learning during cancer treatment.
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