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TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling

Rongxuan Zhu1, Olivier Gires2, Liqun Zhu3

  • 1Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.

Nature Communications
|June 30, 2019
PubMed

Insights

TSPAN8 promotes cancer stemness by enhancing Sonic Hedgehog signaling in breast cancer. This protein interaction leads to therapeutic resistance and poor prognosis in patients, revealing a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cancer stem cells (CSCs) drive tumor progression and treatment resistance.
  • The regulation of CSC stemness remains incompletely understood.
  • Identifying novel regulators of CSCs is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the role of TSPAN8 in regulating breast cancer stemness.
  • To elucidate the molecular mechanisms by which TSPAN8 influences CSC behavior.
  • To explore the therapeutic potential of targeting TSPAN8 in breast cancer.

Main Methods:

  • Quantitative analysis of TSPAN8 expression in breast CSCs.
  • Investigation of TSPAN8 interactions with key signaling pathway components (PTCH1, ATXN3).
  • Assessment of CSC stemness markers (NANOG, OCT4, ALDHA1) and chemoresistance.
  • In vivo tumor formation assays in mice.
  • Correlation analysis of gene expression in human breast cancer specimens.

Main Results:

  • TSPAN8 expression is upregulated in breast CSCs and promotes stemness genes (NANOG, OCT4, ALDHA1).
  • TSPAN8 interacts with PTCH1, stabilizing the SHH/PTCH1 complex via ATXN3 recruitment, leading to SMO translocation to cilia.
  • This pathway activation confers chemoresistance to CSCs and enhances tumor formation in vivo.
  • High TSPAN8 and ATXN3 expression correlates with poor prognosis in human breast cancer.

Conclusions:

  • TSPAN8 plays a critical role in maintaining breast CSC stemness through Sonic Hedgehog pathway activation.
  • The TSPAN8/PTCH1/ATXN3 axis represents a novel mechanism driving therapeutic resistance and tumor progression.
  • Targeting TSPAN8 may offer a promising strategy to overcome treatment resistance in breast cancer.

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