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Updated: Jul 23, 2025

Stimulation of Notch Signaling in Mouse Osteoclast Precursors
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Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in

Pei-Chieh Tien1, Xiyue Chen1, Bennett D Elzey2,3

  • 1Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.

Oncogene
|July 11, 2023
PubMed

Insights

Notch signaling activation in dedifferentiated liposarcoma (DDLPS) suppresses PGC-1α, inhibiting mitochondrial function and promoting cancer growth. Restoring PGC-1α reverses these effects, offering a potential therapeutic target for this lethal cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Dedifferentiated liposarcoma (DDLPS) is a rare, lethal cancer lacking identified driver mutations, hindering targeted therapy development.
  • Constitutive Notch signaling activation, via Notch1 intracellular domain overexpression (NICDOE), in murine adipocytes models human DDLPS.
  • The precise mechanisms of Notch activation's oncogenic role in DDLPS remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which Notch signaling drives DDLPS.
  • To investigate the link between Notch activation, cellular metabolism, and prognosis in DDLPS.
  • To identify potential therapeutic targets for DDLPS based on Notch signaling pathways.

Main Methods:

  • Analysis of Notch signaling activation in human DDLPS patient samples.
  • Metabolic profiling of murine NICDOE DDLPS cells using respirometry and glycolysis assays.
  • Genetic manipulation to ablate NICDOE or overexpress PGC-1α in DDLPS cells.
  • Assessment of mitochondrial biogenesis, cell growth, and adipogenic differentiation.

Main Results:

  • Notch signaling is activated in a subset of human DDLPS, correlating with poor prognosis and MDM2 expression.
  • Murine NICDOE DDLPS cells exhibit reduced mitochondrial respiration and increased glycolysis (Warburg effect).
  • Notch activation diminishes peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression, a key regulator of mitochondrial biogenesis.
  • Genetic rescue of NICDOE or PGC-1α overexpression restored mitochondrial function, inhibited tumor growth, and promoted adipogenic differentiation.

Conclusions:

  • Notch signaling activation in DDLPS suppresses PGC-1α, leading to impaired mitochondrial biogenesis and a metabolic shift towards glycolysis.
  • Restoration of PGC-1α function can reverse the metabolic and proliferative phenotypes of DDLPS.
  • Targeting the Notch-PGC-1α axis represents a promising therapeutic strategy for DDLPS.

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