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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
Hippo Pathway Regulation and Microenvironmental Cues Governing Human MSC Transition to Cancer-Associated Fibroblasts
Pimjai Chingsuwanrote1, Chanchao Lorthongpanich1,2, Pakpoom Kheolamai3
1Department of Medicine, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Three-dimensional culture, hypoxia, and cancer factors transform human mesenchymal stem cells (hMSCs) into inflammatory cancer-associated fibroblasts (iCAFs) by down-regulating YAP/TAZ. This YAP/TAZ regulation is key for hMSC-to-CAF transformation in tumor stroma.
Area of Science:
- Cell Biology
- Cancer Biology
- Stem Cell Biology
Background:
- Cancer-associated fibroblasts (CAFs) are crucial for tumor progression.
- Human mesenchymal stem cells (hMSCs) can differentiate into CAFs.
- Understanding CAF heterogeneity is vital for cancer therapy.
Purpose of the Study:
- To investigate the transformation of hMSCs into inflammatory CAFs (iCAFs).
- To determine the roles of 3D culture, hypoxia, and cancer factors in this transformation.
- To elucidate the underlying molecular mechanisms, focusing on YAP/TAZ signaling.
Main Methods:
- Culturing hMSCs from various sources (bone marrow, placenta, chorion) in 2D and 3D Matrigel systems.
- Exposing cells to hypoxia and soluble factors from colon cancer cell lines (HT29, HCT116).
- Analyzing CAF marker expression (e.g., IL1α, CSF3, IL6, CCN2, MYL9, TAGLN) and YAP/TAZ activity.
- Utilizing genetic depletion of YAP/TAZ to assess its role in hMSC-to-iCAF conversion.
Main Results:
- 3D culture significantly induced iCAF markers while suppressing myofibroblastic CAF markers.
- Hypoxia and cancer factors amplified the iCAF phenotype, increasing IL1α/IL6 secretion.
- These conditions promoted tumor cell growth and angiogenesis.
- YAP/TAZ down-regulation was associated with hMSC-to-iCAF transformation.
- YAP/TAZ depletion alone induced iCAFs in 2D culture.
Conclusions:
- 3D culture, hypoxia, and cancer factors synergistically drive hMSC differentiation into iCAFs.
- YAP/TAZ signaling is a critical regulator of hMSC-to-CAF transformation.
- Targeting YAP/TAZ may offer novel therapeutic strategies for modulating the tumor stroma.
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