Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting

Dev Cell. 2015 Apr 6;33(1):47-55. doi: 10.1016/j.devcel.2015.03.001.

Abstract

Tumors kill patients not only through well-characterized perturbations to their local environment but also through poorly understood pathophysiological interactions with distant tissues. Here, we use a Drosophila tumor model to investigate the elusive mechanisms underlying such long-range interactions. Transplantation of tumors into adults induces robust wasting of adipose, muscle, and gonadal tissues that are distant from the tumor, phenotypes that resemble the cancer cachexia seen in human patients. Notably, malignant, but not benign, tumors induce peripheral wasting. We identify the insulin growth factor binding protein (IGFBP) homolog ImpL2, an antagonist of insulin signaling, as a secreted factor mediating wasting. ImpL2 is sufficient to drive tissue loss, and insulin activity is reduced in peripheral tissues of tumor-bearing hosts. Importantly, knocking down ImpL2, specifically in the tumor, ameliorates wasting phenotypes. We propose that the tumor-secreted IGFBP creates insulin resistance in distant tissues, thus driving a systemic wasting response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Blotting, Western
  • Cachexia / etiology*
  • Cachexia / metabolism
  • Cachexia / pathology
  • Cells, Cultured
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism*
  • Female
  • Humans
  • Image Processing, Computer-Assisted
  • Insulin / metabolism*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Neoplasms, Experimental / complications*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Ovary / metabolism
  • Ovary / pathology
  • Phenotype
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • YAP-Signaling Proteins

Substances

  • Drosophila Proteins
  • Insulin
  • Nuclear Proteins
  • RNA, Messenger
  • Trans-Activators
  • YAP-Signaling Proteins
  • Yki protein, Drosophila
  • Adenosine Triphosphate