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Phase separation of SHP2E76K promotes malignant transformation of mesenchymal stem cells by activating mitochondrial

Chen Kan1, Zhenya Tan1, Liwei Liu2

  • 1Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China.

JCI Insight
|March 7, 2024
PubMed

Insights

Activating mutations in SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) drive sarcoma stem-like cell formation by causing mitochondrial hyperactivation. Inhibiting SHP2 liquid-liquid phase separation (LLPS) offers a potential cancer therapy target.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Mesenchymal stem cells (MSCs) can undergo malignant transformation and aberrant differentiation.
  • The protein tyrosine phosphatase SHP2 regulates cell differentiation, proliferation, and transformation, but its role in MSC fate is unknown.
  • Activating mutations in SHP2 are implicated in various cancers.

Purpose of the Study:

  • To investigate the role of the activating SHP2E76K mutation in MSC fate determination.
  • To elucidate the mechanism by which SHP2E76K mutation drives malignant transformation.
  • To explore SHP2 LLPS as a potential therapeutic target.

Main Methods:

  • Analysis of mouse MSCs with the SHP2E76K mutation.
  • Assessment of mitochondrial metabolism and complex I and III activity.
  • Investigation of SHP2 liquid-liquid phase separation (LLPS) using mutations and inhibitors.

Main Results:

  • MSCs with the SHP2E76K mutation transformed into sarcoma stem-like cells.
  • SHP2E76K mutation caused hyperactive mitochondrial metabolism via activation of complexes I and III.
  • SHP2 LLPS was observed in SHP2E76K MSCs, leading to complex I and III hyperactivation and malignant transformation.

Conclusions:

  • SHP2 LLPS drives mitochondrial hyperactivation, promoting malignant transformation of SHP2E76K MSCs.
  • Inhibition of mitochondrial complexes I and III or SHP2 LLPS prevents malignant transformation.
  • Targeting SHP2 LLPS presents a potential therapeutic strategy for SHP2-associated cancers.
Keywords:
Adult stem cellsCancerMouse stem cellsOncologyStem cells

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