The atypical KRASQ22K mutation directs TGF-β response towards partial epithelial-to-mesenchymal transition in patient-derived colorectal cancer tumoroids
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View abstract on PubMed
Summary
This summary is machine-generated.Transforming growth factor beta (TGF-β) has dual roles in cancer. This study shows TGF-β
Area Of Science
- Oncology
- Cell Biology
- Molecular Biology
Background
- Transforming growth factor beta (TGF-β) exhibits context-dependent roles in cancer, acting as tumor-suppressive in early stages and tumor-promoting in advanced disease.
- The precise mechanisms by which TGF-β influences tumor invasion and metastasis, particularly whether it acts directly on cancer cells or indirectly via the stroma, remain incompletely understood.
- Understanding the duality of TGF-β is crucial for developing effective cancer therapies.
Purpose Of The Study
- To investigate cancer cell-specific responses to TGF-β using patient-derived tumoroids (PDTs) across various colorectal cancer (CRC) stages.
- To elucidate the role of intrinsic cancer cell responses to TGF-β in determining its tumor-suppressive or tumor-promoting effects.
- To explore the molecular mechanisms underlying TGF-β-mediated invasion and metastasis in CRC.
Main Methods
- Utilized a library of colorectal cancer patient-derived tumoroids (PDTs) representing a spectrum of tumor stages.
- Applied differentiation conditions to PDTs to assess TGF-β responses.
- Analyzed molecular changes, including gene expression and pathway deregulation, in response to TGF-β treatment, particularly in a KRAS mutant line.
Main Results
- TGF-β demonstrated tumor-suppressive effects in early-stage CRC tumoroids.
- Advanced-stage tumoroids exhibited reduced sensitivity to TGF-β treatment.
- A KRAS<sup>Q22K</sup> mutant tumoroid line showed partial epithelial-to-mesenchymal transition (EMT), increased invasiveness, elevated mesenchymal gene expression, and altered matrix remodeling and cell adhesion pathways upon TGF-β exposure.
Conclusions
- Tumor cell-intrinsic responses to TGF-β are critical determinants of its tumor-suppressive or tumor-promoting functions in colorectal cancer.
- TGF-β can promote invasion and metastasis in advanced CRC, potentially through direct effects on cancer cells exhibiting specific mutations like KRAS<sup>Q22K</sup>.
- These findings highlight the importance of considering cancer cell-specific responses when evaluating the role of TGF-β in tumorigenesis and metastasis.
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