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

Wei Song1, Serkan Kir2, Shangyu Hong3

  • 1Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Developmental Cell
|January 15, 2019
PubMed

Insights

Tumors cause body wasting by activating MEK signaling in host tissues. Suppressing host MEK signaling resolves wasting without impacting tumor growth, revealing a key mechanism in cancer cachexia.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Research

Background:

  • Tumor-host interactions drive systemic wasting and cancer cachexia, involving muscle wasting and lipid loss.
  • The precise molecular pathways underlying cancer-induced wasting remain incompletely understood.
  • Investigating these mechanisms is crucial for developing therapeutic strategies against cachexia.

Purpose of the Study:

  • To elucidate the molecular mechanisms of tumor-induced organ wasting using a Drosophila model.
  • To identify the role of MEK signaling in both tumor progression and host tissue wasting.
  • To explore therapeutic targets for mitigating cancer cachexia.

Main Methods:

  • Utilized a Drosophila melanogaster model with gut-yki3SA tumors to study tumor-induced organ wasting.
  • Analyzed MEK (MAPK kinase) activation in both tumor and host tissues.
  • Investigated the function of specific ligands (vein and Pvf1) in mediating tumor growth and host responses.
  • Assessed the impact of manipulating MEK signaling on wasting phenotypes and tumor growth.

Main Results:

  • Aberrant MEK activation was observed in both tumor and host tissues of flies with gut-yki3SA tumors.
  • Host MEK activation directly correlates with muscle wasting and lipid loss.
  • Tumor MEK activation is essential for tumor growth.
  • Suppression of host MEK signaling effectively eliminates wasting phenotypes without affecting tumor growth.
  • yki3SA tumors secrete vein (vn) ligand for autonomous Egfr/MEK-mediated tumor growth.
  • yki3SA tumors secrete Pvf1 ligand, non-autonomously activating host Pvr/MEK signaling and causing wasting.

Conclusions:

  • Differential MEK activation in tumor and host tissues plays critical roles in tumor-induced wasting.
  • Host MEK signaling is a key mediator of cancer cachexia, specifically muscle wasting and lipid loss.
  • Targeting host MEK signaling presents a potential therapeutic strategy for cancer cachexia without compromising anti-tumor effects.
Keywords:
ERKMEKPvf1Pvrcancer cachexialipid lossmuscle wastingsecreted proteinstumor-host interactiontumor-induced wasting

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