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Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer
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DIO3 associates with sorting nexins and endosomal trafficking networks in ovarian cancer

Daniel Maman-Shinar1,2, Shachar Vanmak1,2, David Bern3

  • 1Translational Oncology Research, The Oncology Institute, Meir Medical Center, Kfar-Saba, 44821, Israel.

Cellular Oncology (Dordrecht, Netherlands)
|June 2, 2026
PubMed
Abstract

Insights

Sorting nexins SNX2 and SNX6 regulate the trafficking and stability of type 3 iodothyronine deiodinase (DIO3) in ovarian cancer. Targeting these pathways offers a new therapeutic vulnerability for high-grade serous ovarian cancer (HGSOC).

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Mechanisms

Background:

  • Type 3 iodothyronine deiodinase (DIO3) inactivates thyroid hormones and promotes high-grade serous ovarian cancer (HGSOC) progression.
  • The intracellular trafficking and stability mechanisms of DIO3 are currently unknown.

Purpose of the Study:

  • To elucidate the mechanisms governing DIO3 intracellular routing and functional stability.
  • To identify key regulators of DIO3 trafficking in ovarian cancer.

Main Methods:

  • Utilized human ovarian cancer cell lines, patient tumors, and immortalized fallopian tube cells.
  • Employed gene knockdown (shRNA) and overexpression (CRISPR activation) of DIO3.
  • Performed flow cytometry, proteomics, co-immunoprecipitation, proximity ligation assay, confocal imaging, and AlphaFold structural modeling.

Main Results:

  • Identified sorting nexins SNX2 and SNX6 as crucial components of the DIO3 trafficking machinery.
  • Structural analysis revealed a potential interface for SNXs association with DIO3.
  • Demonstrated that SNX6 facilitates endosomal/Golgi progression, while SNX2 mediates plasma membrane recycling via RAB11 vesicles.
  • Disruption of DIO3-SNXs colocalization selectively impaired proliferation and survival of DIO3-overexpressing cells.

Conclusions:

  • Intracellular trafficking is a key determinant of DIO3 stability and function in ovarian cancer.
  • Sorting nexin-mediated routing of DIO3 represents a novel dependency and therapeutic vulnerability in HGSOC.
Keywords:
DeiodinasesOvarian cancerRecyclingTrafficking

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