Interaction between Ras and Src clones causes interdependent tumor malignancy via Notch signaling in Drosophila

Dev Cell. 2021 Aug 9;56(15):2223-2236.e5. doi: 10.1016/j.devcel.2021.07.002. Epub 2021 Jul 28.

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.

Keywords: Notch signaling; Ras; Src; cell-cell interaction; tumor heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Neoplasms / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Oncogene Protein pp60(v-src) / metabolism*
  • Oncogene Protein pp60(v-src) / physiology
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Proto-Oncogene Proteins p21(ras) / physiology
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction / physiology
  • Transcription Factors / metabolism
  • Zinc Fingers

Substances

  • Cadherins
  • Chinmo protein, Drosophila
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • N protein, Drosophila
  • Nerve Tissue Proteins
  • Receptors, Notch
  • Repressor Proteins
  • Transcription Factors
  • delta protein
  • upd1 protein, Drosophila
  • zfh1 protein, Drosophila
  • Oncogene Protein pp60(v-src)
  • Proto-Oncogene Proteins p21(ras)