Epithelial neoplasia in Drosophila entails switch to primitive cell states

Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):E2163-72. doi: 10.1073/pnas.1212513110. Epub 2013 May 24.

Abstract

Only select cell types in an organ display neoplasia when targeted oncogenically. How developmental lineage hierarchies of these cells prefigure their neoplastic propensities is not yet well-understood. Here we show that neoplastic Drosophila epithelial cells reverse their developmental commitments and switch to primitive cell states. In a context of alleviated tissue surveillance, for example, loss of Lethal giant larvae (Lgl) tumor suppressor in the wing primordium induced epithelial neoplasia in its Homothorax (Hth)-expressing proximal domain. Transcriptional profile of proximally transformed mosaic wing epithelium and functional tests revealed tumor cooperation by multiple signaling pathways. In contrast, lgl(-) clones in the Vestigial (Vg)-expressing distal wing epithelium were eliminated by cell death. Distal lgl(-) clones, however, could transform when both tissue surveillance and cell death were compromised genetically and, alternatively, when the transcription cofactor of Hippo signaling pathway, Yorkie (Yki), was activated, or when Ras/EGFR signaling was up-regulated. Furthermore, transforming distal lgl(-) clones displayed loss of Vg, suggesting reversal of their terminal cell fate commitment. In contrast, reinforcing a distal (wing) cell fate commitment in lgl(-) clones by gaining Vg arrested their neoplasia and induced cell death. We also show that neoplasia in both distal and proximal lgl(-) clones could progress in the absence of Hth, revealing Hth-independent wing epithelial neoplasia. Likewise, neoplasia in the eye primordium resulted in loss of Elav, a retinal cell marker; these, however, switched to an Hth-dependent primitive cell state. These results suggest a general characteristic of "cells-of-origin" in epithelial cancers, namely their propensity for switch to primitive cell states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics
  • Cell Transformation, Neoplastic / genetics
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / growth & development
  • Epithelial Cells / metabolism*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Microscopy, Fluorescence
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Wings, Animal / cytology
  • Wings, Animal / growth & development
  • Wings, Animal / metabolism
  • YAP-Signaling Proteins

Substances

  • Drosophila Proteins
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Trans-Activators
  • Tumor Suppressor Proteins
  • YAP-Signaling Proteins
  • Yki protein, Drosophila
  • hth protein, Drosophila
  • l(2)gl protein, Drosophila
  • vg protein, Drosophila
  • Green Fluorescent Proteins
  • ErbB Receptors
  • Protein Serine-Threonine Kinases
  • hpo protein, Drosophila