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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
PubMed

Insights

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.
Keywords:
APOBEC3AZNF750episodic gene expressionkeratinocyte differentiationlineage plasticitymutational signaturestranscriptional reprogramming

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