Squamous-state excursions activate APOBEC3A in cancer.
Josefine Striepen1, Alexandra Dananberg1, Aušrinė Ruzgaitė1
1Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Biorxiv : the Preprint Server for Biology
|June 5, 2026
Summary
Cytidine deaminase APOBEC3A drives cancer mutations during transient squamous differentiation, not inflammation. This cell plasticity links to cancer genome evolution, explaining APOBEC3A
Area of Science:
- Cancer Biology
- Genetics
- Cellular Differentiation
Background:
- APOBEC3A (cytidine deaminase) is a significant endogenous mutagen in human cancer.
- Its mutational signatures are evident in cancer genomes, but expression is often missed in bulk analyses.
- The source of APOBEC3A's episodic mutagenic activity has been attributed to inflammatory signaling.
Purpose of the Study:
- To investigate the cellular origin and regulation of APOBEC3A-driven mutagenesis in cancer.
- To link APOBEC3A activity to specific cellular states and signaling pathways.
- To understand the role of lineage-state plasticity in cancer genome evolution.
Main Methods:
- Analysis of APOBEC3A expression in breast and lung cancer cell lines and patient tumors.
- Correlation of APOBEC3A levels with keratinocyte differentiation markers (KRT6A, KRT16).
- Investigation of APOBEC3A's catalytic activity effects on signaling pathways (JNK-AP-1).
- Role of transcription factor ZNF750 in APOBEC3A regulation during differentiation.
Main Results:
- APOBEC3A is induced in a rare subpopulation of cancer cells undergoing transient squamous differentiation.
- Squamous differentiation markers strongly correlate with APOBEC3A expression, explaining its transient nature.
- APOBEC3A activity reinforces squamous differentiation via uracil excision and JNK-AP-1 signaling.
- ZNF750 promotes APOBEC3A induction in models, but its loss elevates APOBEC3A in human squamous tumors.
Conclusions:
- Transient squamous differentiation, a form of cell-state plasticity, is a key driver of APOBEC3A mutagenesis.
- This mechanism explains how APOBEC3A leaves mutational scars while evading bulk detection.
- Lineage-context-dependent regulation of APOBEC3A by ZNF750 influences cancer genome evolution.
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