A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors

Dis Model Mech. 2020 Jul 23;13(7):dmm044420. doi: 10.1242/dmm.044420.

Abstract

Peptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven intestinal stem cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.This article has an associated First Person interview with the first author of the paper.

Keywords: Drosophila; Integrin signaling; Intestinal stem cells; Peptide therapeutic; Yki.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / metabolism
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / administration & dosage*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / drug effects*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Drug Development*
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intestinal Neoplasms / drug therapy*
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / pathology
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • PC-3 Cells
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / administration & dosage*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • YAP-Signaling Proteins

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Nuclear Proteins
  • Peptide Fragments
  • Trans-Activators
  • Transcription Factors
  • VGLL1 protein, human
  • YAP-Signaling Proteins
  • Yki protein, Drosophila
  • esg protein, Drosophila
  • sd protein, Drosophila