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Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

Chiswili Chabu1, Tian Xu2

  • 1Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.

Development (Cambridge, England)
|November 21, 2014
PubMed

Insights

Oncogenic Ras promotes cancer by blocking cell death and stimulating growth. Inhibiting Eiger/TNF exocytosis or JNK-JAK-STAT signaling suppresses this Ras-driven tumor overgrowth.

Area of Science:

  • Oncology
  • Cell Biology
  • Genetics

Background:

  • Oncogenic Ras mutations drive cancer by disrupting cell death and proliferation.
  • Cancers with oncogenic Ras are often aggressive and treatment-resistant.
  • Mechanisms of oncogenic Ras effects and therapeutic targets remain incompletely understood.

Purpose of the Study:

  • To identify novel suppressors of oncogenic Ras in vivo.
  • To elucidate the role of exocytosis in oncogenic Ras signaling.
  • To explore new therapeutic strategies for Ras-driven cancers.

Main Methods:

  • Utilized a Drosophila mosaic screen to identify synthetic suppressors of oncogenic Ras.
  • Investigated the impact of oncogenic Ras on exocytosis and pro-apoptotic ligand export.
  • Analyzed the role of the JNK-JAK-STAT signaling pathway in non-autonomous proliferation.

Main Results:

  • Identified Sec15, an exocytosis component, as a synthetic suppressor of oncogenic Ras.
  • Oncogenic Ras was found to increase exocytosis and Eiger (Drosophila TNF) export, blocking tumor cell death.
  • This process stimulated overgrowth via JNK-JAK-STAT signaling in neighboring cells.
  • Inhibiting Eiger/TNF exocytosis or JNK-JAK-STAT signaling suppressed oncogenic Ras-mediated overgrowth.

Conclusions:

  • Exocytosis plays critical cell-intrinsic and cell-extrinsic roles in oncogenic Ras-driven growth.
  • Targeting Eiger/TNF exocytosis or JNK-JAK-STAT signaling offers potential therapeutic avenues.
  • Discovered a new class of synthetic suppressors for oncogenic Ras-driven cancers.
Keywords:
EigerExocytosisOncogenic RasTNFTumors

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