RRC ID 67269
Author Enomoto M, Takemoto D, Igaki T.
Title Interaction between Ras and Src clones causes interdependent tumor malignancy via Notch signaling in Drosophila.
Journal Dev Cell
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.
Volume 56(15)
Pages 2223-2236.e5
Published 2021-8-9
DOI 10.1016/j.devcel.2021.07.002
PII S1534-5807(21)00558-X
PMID 34324859
MeSH 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
IF 10.092
Drosophila 5993R-2 1322R-1 1322R-2 DGRC#109005