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Cell Type-Specific Transcriptome Profiling Reveals a Role for Thioredoxin During Tumor Initiation.

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Area of Science:

  • Oncology
  • Immunology
  • Developmental Biology
  • Zebrafish Models

Background:

  • Neutrophil function is altered in the tumor microenvironment.
  • Neutrophil behavior during early tumor initiation is not well understood.

Purpose of the Study:

  • To investigate transcriptional changes in neutrophils, macrophages, and transformed epithelial cells during oncogenic Ras-induced tumor initiation in zebrafish.
  • To determine the role of thioredoxin in neutrophil behavior and transformed cell proliferation during tumor initiation.

Main Methods:

  • Translating Ribosomal Affinity Purification (TRAP) and RNA sequencing were employed to analyze gene expression.
  • Zebrafish thioredoxin mutants were generated to study thioredoxin's function.
  • Live imaging was used to visualize neutrophil behavior near transformed cells.

Main Results:

  • Oncogenic Ras induced significant gene expression changes in neutrophils and transformed epithelial cells, but not macrophages.
  • Thioredoxin was upregulated in transformed keratinocytes and neutrophils.
  • Thioredoxin deficiency led to increased reactive oxygen species signaling, enhanced neutrophil recruitment, increased transformed keratinocyte proliferation, and reduced apoptosis.
  • Neutrophil absence abrogated the increased proliferation of transformed keratinocytes in thioredoxin mutants.

Conclusions:

  • Tumor initiation alters neutrophil gene expression and behavior.
  • Neutrophils play a critical role in regulating transformed cell proliferation during early tumor development.
  • Thioredoxin influences neutrophil recruitment and function, impacting early tumor progression.