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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
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Mutant FOXL2C134W Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors

Stine E Weis-Banke1,2, Mads Lerdrup3, Daniela Kleine-Kohlbrecher1,2

  • 1Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark.

Cancer Research
|July 10, 2020
PubMed

Insights

The FOXL2C134W mutation drives ovarian tumors by hijacking SMAD4, activating genes for epithelial-to-mesenchymal transition. Targeting FOXL2C134W and TGFβ offers new therapeutic strategies for adult-type granulosa cell tumors (AGCT).

Area of Science:

  • Molecular Oncology
  • Cancer Genomics
  • Epigenetics

Background:

  • The FOXL2C134W mutant protein is a key driver in over 95% of adult-type ovarian granulosa cell tumors (AGCT).
  • The precise molecular mechanisms by which FOXL2C134W promotes tumorigenesis remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism of FOXL2C134W-driven oncogenesis in AGCT.
  • To identify potential therapeutic targets based on the identified molecular interactions.

Main Methods:

  • Analysis of FOXL2C134W protein interactions with SMAD4 and SMAD2/3.
  • Identification of novel DNA binding motifs for the FOXL2C134W/SMAD complex.
  • Assessment of chromatin states and gene expression changes upon FOXL2C134W binding.
  • Experimental ablation of SMAD4 or SMAD2/3 and inhibition of TGFβ signaling.

Main Results:

  • Mutant FOXL2C134W forms a complex with SMAD4/SMAD2/3, binding a unique AGHCAHAA DNA motif.
  • This interaction induces an enhancer-like chromatin state, activating genes associated with epithelial-to-mesenchymal transition (EMT).
  • SMAD4/SMAD2/3 ablation or TGFβ inhibition significantly reduces FOXL2C134W binding and target gene expression.

Conclusions:

  • FOXL2C134W oncogenesis in AGCT involves hijacking the SMAD4 pathway to promote EMT and stemness.
  • The FOXL2C134W-SMAD4 interaction and the TGFβ pathway represent promising therapeutic targets for AGCT.

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