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FUS-DDIT3 Fusion Oncoprotein Expression Affects JAK-STAT Signaling in Myxoid Liposarcoma

Soheila Dolatabadi1, Emma Jonasson1, Lisa Andersson1

  • 1Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Frontiers in Oncology
|February 21, 2022
PubMed

Insights

The FUS-DDIT3 oncogene in myxoid liposarcoma activates JAK-STAT signaling, influencing cancer stem cell properties and potentially driving tumor progression. This discovery offers new therapeutic targets for sarcomas and leukemia.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Myxoid liposarcoma, a common sarcoma, often exhibits FET fusion oncogenes.
  • Chemotherapy resistance is a significant clinical challenge in myxoid liposarcoma.
  • Cancer stem cell properties are linked to JAK-STAT signaling, but its connection to the FUS-DDIT3 oncogene is unclear.

Purpose of the Study:

  • To investigate the functional link between the FUS-DDIT3 oncogene and JAK-STAT signaling in myxoid liposarcoma.
  • To identify molecular mechanisms underlying tumor progression driven by FUS-DDIT3.
  • To explore potential therapeutic targets for FUS-DDIT3-driven cancers.

Main Methods:

  • Ectopic expression of FUS-DDIT3 and analysis of STAT3 phosphorylation.
  • RNA sequencing to identify genes regulated by FUS-DDIT3 and JAK1/2 inhibition (ruxolitinib).
  • Protein-protein interaction studies and analysis of public chromatin immunoprecipitation sequencing data.

Main Results:

  • FUS-DDIT3 expression elevated STAT3 and phosphorylated STAT3 levels.
  • 126 genes were identified as co-regulated by FUS-DDIT3 and JAK1/2 inhibition, forming a protein interaction network.
  • CD44 was validated as a JAK1/2 inhibition target and potential cancer stem cell marker; FUS-DDIT3 interacts with pSTAT3 and chromatin remodeling complexes.

Conclusions:

  • FUS-DDIT3 oncogene function is closely linked to JAK-STAT signaling pathways.
  • Understanding these molecular mechanisms provides new avenues for targeted therapies in sarcomas and leukemia with FET fusion oncogenes.
  • The study highlights CD44 as a potential therapeutic target and biomarker in myxoid liposarcoma.
Keywords:
CD44FET sarcomasFUS-DDIT3JAK-STAT signalingcancer stem cellsmyxoid liposarcoma

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