1. Interaction between Ras and Src clones causes interdependent tumor malignancy via Notch signaling in Drosophila.
- Author
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Enomoto M, Takemoto D, and Igaki T
- Subjects
- Animals, Cadherins metabolism, Carcinogenesis metabolism, Cell Transformation, Neoplastic genetics, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Epithelium metabolism, Gene Expression Regulation, Neoplastic genetics, Genes, ras genetics, Genes, ras physiology, Imaginal Discs metabolism, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Nerve Tissue Proteins metabolism, Oncogene Protein pp60(v-src) physiology, Proto-Oncogene Proteins p21(ras) physiology, Receptors, Notch genetics, Receptors, Notch metabolism, Repressor Proteins metabolism, Signal Transduction physiology, Transcription Factors metabolism, Zinc Fingers, Neoplasms metabolism, Oncogene Protein pp60(v-src) metabolism, Proto-Oncogene Proteins p21(ras) metabolism
- Abstract
Cancer tissue often comprises multiple tumor clones with distinct oncogenic alterations such as Ras or Src activation, yet the mechanism by which tumor heterogeneity drives cancer progression remains elusive. Here, we show in Drosophila imaginal epithelium that clones of Ras- or Src-activated benign tumors interact with each other to mutually promote tumor malignancy. Mechanistically, Ras-activated cells upregulate the cell-surface ligand Delta while Src-activated cells upregulate its receptor Notch, leading to Notch activation in Src cells. Elevated Notch signaling induces the transcriptional repressor Zfh1/ZEB1, which downregulates E-cadherin and cell death gene hid, leading to Src-activated invasive tumors. Simultaneously, Notch activation in Src cells upregulates the cytokine Unpaired/IL-6, which activates JAK-STAT signaling in neighboring Ras cells. Elevated JAK-STAT signaling upregulates the BTB-zinc-finger protein Chinmo, which downregulates E-cadherin and thus generates Ras-activated invasive tumors. Our findings provide a mechanistic explanation for how tumor heterogeneity triggers tumor progression via cell-cell interactions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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