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Updated: Jan 20, 2026

3-D Cell Culture System for Studying Invasion and Evaluating Therapeutics in Bladder Cancer
09:24

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Published on: September 13, 2018

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Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells

Sreeharsha Gurrapu1, Giulia Franzolin1,2, Damon Fard1,2

  • 1Cancer Cell Biology Laboratory, Candiolo Cancer Institute-FPO, IRCCS, Candiolo 10060, Italy.

Science Signaling
|August 22, 2019
PubMed

Insights

Transmembrane semaphorin 4C (Sema4C) exhibits a novel reverse signaling role in cancer. This Sema4C reverse signaling promotes gene reprogramming and phenotypic plasticity, driving metastatic behavior in invasive carcinoma cells.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Cancer research

Background:

  • Semaphorins are key regulators of cell migration.
  • Transmembrane semaphorins can signal in both forward and reverse modes.
  • Reverse semaphorin signaling in cancer remains less understood.

Purpose of the Study:

  • To investigate the role of transmembrane semaphorin 4C (Sema4C) in reverse signaling within cancer.
  • To elucidate the molecular mechanisms underlying Sema4C reverse signaling.
  • To determine the impact of Sema4C reverse signaling on cancer cell behavior and gene expression.

Main Methods:

  • Co-immunoprecipitation assays to assess protein interactions.
  • Analysis of SMAD1/5 phosphorylation.
  • Quantitative PCR and gene expression profiling.
  • In vivo metastasis assays.

Main Results:

  • Sema4C was identified to function in reverse mode, activating nonconventional TGF-β/BMP receptor pathways.
  • Sema4C coimmunoprecipitated with TGFBRII and BMPR1.
  • Sema4C reverse signaling induced SMAD1/5 phosphorylation and increased ID1/3 transcriptional factors.
  • This reprogramming suppressed epithelial-mesenchymal transition features but enhanced metastatic potential in vivo.
  • Sema4C expression correlated with metastatic progression in human breast cancers.

Conclusions:

  • Sema4C reverse signaling modulates TGF-β/BMP pathways via SMAD1/5 phosphorylation.
  • Sema4C-driven gene expression reprogramming contributes to phenotypic plasticity and metastatic behavior in invasive cancer cells.
  • Sema4C represents a potential therapeutic target for inhibiting cancer metastasis.

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