Zebrafish imaging reveals hidden oncogenic-normal cell communication during primary tumorigenesis

Abstract

Oncogenic mutations drive tumorigenesis, and single cells with oncogenic mutations act as the tumor seeds that gradually evolve into fully transformed tumors. However, oncogenic cell behavior and communication with neighboring cells during primary tumorigenesis remain poorly understood. We used the zebrafish, a small vertebrate model suitable for in vivo cell biology, to address these issues. We describe the cooperative and competitive communication between oncogenic cells and neighboring cells, as revealed by our recent zebrafish imaging studies. Newly generated oncogenic cells are actively eliminated by neighboring cells in healthy epithelia, whereas oncogenic cells cooperate with their neighbors to prime tumorigenesis in unhealthy epithelia via additional mutations or inflammation. In addition, we discuss the potential of zebrafish in vivo imaging to determine the initial steps of human tumorigenesis.Key words: zebrafish, imaging, cell-cell communication, cell competition, EDAC, senescence, primary tumorigenesis.

Keywords: EDAC; cell competition; cell-cell communication; imaging; primary tumorigenesis; senescence; zebrafish.

Fig. 1

Schematic illustration of the mosaic introduction of oncogenic cells on zebrafish larval skin Abbreviations: UAS, upstream activation sequence; 2A, 2A self-cleaving peptides; krt4, keratin4.

Fig. 2

Schematic illustration of the mechanisms of mosaic Ras mutant cell elimination from zebrafish skin

Fig. 3

Schematic illustration of three anti-tumorigenic roles of cellular senescence (A) The induction of irreversible cell cycle arrest in oncogenic cells, (B) The stimulation of immune cell-mediated senescent cell elimination, and (C) Neighboring normal cell-mediated elimination of oncogenic cells.

Fig. 4

Schematic illustration of three mechanisms of OIS (A) Oncogenic signaling-induced cellular senescence in a cell-autonomous manner. (B) Senesced oncogenic cells spread senescence to neighboring cells through cell-cell communication. (C) Intercellular communication with neighboring normal cells accelerated senescence in oncogenic signaling-activated cells.

Fig. 5

Schematic illustration of the behaviors of Ras mutant and Ras-TP53 double mutant cells and their neighboring cells on healthy and unhealthy epithelia

Fig. 6

Schematic illustration of the fate of Ras or Wnt mutant cells and the effects of additional mutations in tumor-suppressor genes and inflammation