title: Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut.
abstract: Inactivating mutations within adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, are responsible for most sporadic and hereditary forms of colorectal cancer (CRC). Here, we use the adult Drosophila midgut as a model system to investigate the molecular events that mediate intestinal hyperplasia following loss of Apc in the intestine. Our results indicate that the conserved Wnt target Myc and its binding partner Max are required for the initiation and maintenance of intestinal stem cell (ISC) hyperproliferation following Apc1 loss. Importantly, we find that loss of Apc1 leads to the production of the interleukin-like ligands Upd2/3 and the EGF-like Spitz in a Myc-dependent manner. Loss of Apc1 or high Wg in ISCs results in non-cell-autonomous upregulation of upd3 in enterocytes and subsequent activation of Jak/Stat signaling in ISCs. Crucially, knocking down Jak/Stat or Spitz/Egfr signaling suppresses Apc1-dependent ISC hyperproliferation. In summary, our results uncover a novel non-cell-autonomous interplay between Wnt/Myc, Egfr and Jak/Stat signaling in the regulation of intestinal hyperproliferation. Furthermore, we present evidence suggesting potential conservation in mouse models and human CRC. Therefore, the Drosophila adult midgut proves to be a powerful genetic system to identify novel mediators of APC phenotypes in the intestine.
authors.affiliation: Wnt Signaling and Colorectal Cancer Group, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. j.cordero@beatson.gla.ac.uk
authors.forename: Julia B
authors.initials: JB
authors.lastname: Cordero
authors.forename: Rhoda K
authors.initials: RK
authors.lastname: Stefanatos
authors.forename: Kevin
authors.initials: K
authors.lastname: Myant
authors.forename: Marcos
authors.initials: M
authors.lastname: Vidal
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006965:Hyperplasia / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000502:physiology; D018010:Receptors, Invertebrate Peptide / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D064189:Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome; D029721:Drosophila Proteins; D018010:Receptors, Invertebrate Peptide; D050791:STAT Transcription Factors; C577334:Shtd protein, Drosophila; D014157:Transcription Factors; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors; D053612:Janus Kinases; C085845:hop protein, Drosophila