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Cancer research

TGF-b Ligands Paradoxically Promote Cancer Invasion and Metastasis in Colon Cancer

Strategic Insights

— 2 min read

A recent study published in Scientific Reports has revealed that TGF-b ligands can suppress growth in colon cancer cells yet promote invasion and metastasis in certain contexts. The researchers, led by Dr. Mirvat Surakhy at the University of Oxford, characterized phenotypes and associated gene expression signatures in conditional murine intestinal adenoma with and without Smad4. The study found that loss of Smad4 led to a paradoxical increase in cancer invasion and metastasis, with the development of large non-metastatic caecal adenoma. The researchers also identified Smad4-dependent gene expression signatures that correlated with poorer survival in colorectal cancer patients.

Key Takeaways:

  • The TGF-b ligands can have a dual role in colon cancer, suppressing growth yet promoting invasion and metastasis depending on the downstream pathway mutational context.
  • Loss of Smad4 led to a paradoxical increase in cancer invasion and metastasis, with the development of large non-metastatic caecal adenoma.
  • The researchers identified Smad4-dependent gene expression signatures that correlated with poorer survival in colorectal cancer patients, including SMAD4 low, ID1 low, SPP1 high, and PAK3 high.
  • The study suggested that Smad4-dependent gene expression signatures could be used as functional biomarker classifiers of SMAD4 mutated cancer subtypes.
  • The research provided new insights into the complex role of TGF-b ligands in colon cancer and highlighted the need for further evaluation of Smad4-dependent gene expression signatures as biomarkers for SMAD4 mutated cancer subtypes.
  • The study was funded by the Oxford Clarendon-Islamic Development Bank, Rhodes Trust, Oxford, and Cancer Research UK.
  • The research concluded that murine adenoma identified Smad4-dependent gene expression signatures that require further evaluation to determine their potential as biomarkers for SMAD4 mutated cancer subtypes.

Statistics:

  • 76 Smad4 and TGF-b1 dependent genes were identified in Apc fl/fl Smad4 fl/fl adenoma organoids.
  • Only 7 human equivalent genes were differentially expressed in SMAD4 mutated colorectal cancer (TCGA cohorts), including ID1 low.
  • The IC50 for TGF-b1 dose-dependent growth arrest and cell death in Apc D/D Smad4 +/+ adenoma organoids was 24 pM.
  • The IC50 for TGF-b1 dose-dependent growth arrest and cell death in Apc D/D Smad4 D/D adenoma organoids was 534 pM.
  • The expression of ID1 low and SPP1 high genes was significantly altered in Apc D/D Smad4 D/D adenoma organoids.
  • The study identified expansion of Lgr5 low, Pak3 high, and Id1 low progenitor populations in Apc D/D Smad4 D/D adenoma.

Sources:

  • Smad4 and TGFb1 dependent gene expression signatures in conditional intestinal adenoma, organoids and colorectal cancer. Scientific Reports, 2025,15(1):1-19. (Scientific Reports - http://www.nature.com/srep/index.html)
  • NewsRx. New Colon Cancer Data Have Been Reported by Researchers at University of Oxford (Smad4 and TGFb1 dependent gene expression signatures in conditional intestinal adenoma, organoids and colorectal cancer). Health & Medicine Week. May 30, 2025; p 2646.

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