Tumor-Derived Ligands Trigger Tumor Growth and Host Wasting via Differential MEK Activation

Dev Cell. 2019 Jan 28;48(2):277-286.e6. doi: 10.1016/j.devcel.2018.12.003. Epub 2019 Jan 10.

Abstract

Interactions between tumors and host tissues play essential roles in tumor-induced systemic wasting and cancer cachexia, including muscle wasting and lipid loss. However, the pathogenic molecular mechanisms of wasting are still poorly understood. Using a fly model of tumor-induced organ wasting, we observed aberrant MEK activation in both tumors and host tissues of flies bearing gut-yki3SA tumors. We found that host MEK activation results in muscle wasting and lipid loss, while tumor MEK activation is required for tumor growth. Strikingly, host MEK suppression alone is sufficient to abolish the wasting phenotypes without affecting tumor growth. We further uncovered that yki3SA tumors produce the vein (vn) ligand to trigger autonomous Egfr/MEK-induced tumor growth and produce the PDGF- and VEGF-related factor 1 (Pvf1) ligand to non-autonomously activate host Pvr/MEK signaling and wasting. Altogether, our results demonstrate the essential roles and molecular mechanisms of differential MEK activation in tumor-induced host wasting.

Keywords: ERK; MEK; Pvf1; Pvr; cancer cachexia; lipid loss; muscle wasting; secreted proteins; tumor-host interaction; tumor-induced wasting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cachexia / metabolism*
  • Cell Line, Tumor
  • ErbB Receptors / metabolism
  • Ligands*
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Muscle, Skeletal / metabolism
  • Phosphorylation
  • Signal Transduction / physiology*

Substances

  • Ligands
  • EGFR protein, human
  • ErbB Receptors