Related Experiment Video

Updated: Oct 11, 2025

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

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SMAD4 mutations do not preclude epithelial-mesenchymal transition in colorectal cancer

Patrick Frey1,2,3, Antoine Devisme3,4, Katja Rose1

  • 1Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Oncogene
|December 3, 2021
PubMed

Insights

Cancer cells with SMAD4 mutations can still undergo epithelial-mesenchymal transitions (EMT) independently of TGFβ signaling. Alternative transcription factors compensate for SMAD4 loss, enabling invasion and metastasis in these tumors.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Cellular Signaling

Background:

  • Transforming growth factor beta (TGFβ) superfamily signaling drives epithelial-mesenchymal transitions (EMT), promoting cancer invasion and metastasis.
  • SMAD4, a key transcription factor in TGFβ/BMP signaling, is frequently inactivated in cancers like colorectal cancer (CRC) and pancreatic adenocarcinoma (PAAD).
  • It is widely assumed that SMAD4-mutant (SMAD4mut) cancer cells cannot undergo EMT due to SMAD4's crucial role in its execution.

Purpose of the Study:

  • To investigate whether SMAD4-mutant cancer cells can execute EMT independently of TGFβ signaling.
  • To explore the plasticity of gene regulatory networks in EMT execution.
  • To determine the implications of SMAD4 mutations for EMT in human tumors.

Main Methods:

  • Utilized SMAD4-mutant CRC cell lines to study EMT induction.
  • Assessed morphological changes, invasiveness, and EMT marker gene expression upon SNAIL1 induction.
  • Performed global transcriptome analysis to evaluate SNAIL1-dependent gene regulation.
  • Analyzed human tumor transcriptomes to correlate SMAD4 mutations with EMT signatures.

Main Results:

  • SMAD4mut cells exhibited EMT characteristics, including invasiveness and altered EMT marker gene expression, upon SNAIL1 induction.
  • SNAIL1-induced EMT in SMAD4mut cells was independent of TGFβ/BMP receptor activity.
  • Transcriptome analysis confirmed a robust EMT gene regulatory program in SMAD4mut cells.
  • Human tumor data indicated that SMAD4 mutations are not underrepresented in mesenchymal tumors, with similar EMT gene expression patterns in SMAD4mut and SMAD4 wild-type (SMAD4wt) cases.

Conclusions:

  • Alternative transcription factors can functionally replace SMAD4 downstream of EMT-inducing transcription factors, highlighting the plasticity of EMT regulatory networks.
  • EMT is not entirely precluded in SMAD4-mutant tumors, challenging previous assumptions.
  • These findings have significant implications for the diagnostic and therapeutic evaluation of SMAD4-mutant cancers.

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