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A FoxM1/Smad4 positive feedback loop promotes pancreatic cancer progression
Banzhan Ruan1,2, Bingshu Wang1,3, Xiaodian Zhang1
1Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, Hainan Branch of National Clinical Research Center for Cancer, the First Affiliated Hospital, Hainan Medical University, Haikou, China.
Cell Death & Disease
|April 10, 2026
Summary
FoxM1 stabilizes Smad4 by blocking its degradation, creating a positive feedback loop that drives pancreatic cancer progression via aberrant TGF-β pathway activation. This discovery offers new therapeutic targets for pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Pancreatic cancer is a lethal disease with poor prognosis.
- The transcription factor FoxM1 and the TGF-β/Smad signaling pathway are implicated in pancreatic cancer progression.
- The precise mechanisms of FoxM1 and Smad4 cooperation in regulating TGF-β signaling are not fully understood.
Purpose of the Study:
- To investigate the role of FoxM1 in Smad4 stabilization.
- To elucidate the regulatory mechanisms of TGF-β signaling by FoxM1 and Smad4.
- To identify potential therapeutic targets for pancreatic cancer.
Main Methods:
- Molecular cytology techniques
- Animal models of pancreatic cancer
- Analysis of human pancreatic cancer tissues
Main Results:
- FoxM1 inhibits the ubiquitin-proteasome degradation of Smad4, leading to Smad4 stabilization.
- Smad4 translocates to the nucleus and induces FoxM1 expression, forming a positive feedback loop.
- This feedback loop is upregulated in pancreatic cancer tissues, particularly in poorly differentiated tumors, and aberrantly activates the TGF-β pathway.
Conclusions:
- A novel positive feedback loop between FoxM1 and Smad4 promotes pancreatic cancer progression.
- Aberrant activation of the TGF-β pathway by this loop drives tumor development and migration.
- This FoxM1-Smad4 feedback loop represents a potential therapeutic target for pancreatic cancer treatment.
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