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TGFβ promotes YAP-dependent AXL induction in mesenchymal-type lung cancer cells
Jeong-Yun Choi1, Haeseung Lee2, Eun-Ji Kwon1
1College of Pharmacy, Seoul National University, Korea.
Abstract:
The acquisition of chemoresistance remains a major cause of cancer mortality due to the limited accessibility of targeted or immune therapies. However, given that severe alterations of molecular features during epithelial-to-mesenchymal transition (EMT) lead to acquired chemoresistance, emerging studies have focused on identifying targetable drivers associated with acquired chemoresistance. Particularly, AXL, a key receptor tyrosine kinase that confers resistance against targets and chemotherapeutics, is highly expressed in mesenchymal cancer cells. However, the underlying mechanism of AXL induction in mesenchymal cancer cells is poorly understood. Our study revealed that the YAP signature, which was highly enriched in mesenchymal-type lung cancer, was closely correlated to AXL expression in 181 lung cancer cell lines. Moreover, using isogenic lung cancer cell pairs, we also found that doxorubicin treatment induced YAP nuclear translocation in mesenchymal-type lung cancer cells to induce AXL expression. Additionally, the concurrent activation of TGFβ signaling coordinated YAP-dependent AXL expression through SMAD4. These data suggest that crosstalk between YAP and the TGFβ/SMAD axis upon treatment with chemotherapeutics might be a promising target to improve chemosensitivity in mesenchymal-type lung cancer.
Insights
Chemoresistance in lung cancer is linked to epithelial-to-mesenchymal transition (EMT). This study reveals that YAP signaling and TGFβ/SMAD axis crosstalk drive AXL expression, a key factor in chemoresistance, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemoresistance significantly contributes to cancer mortality, limiting treatment efficacy.
- Epithelial-to-mesenchymal transition (EMT) is associated with acquired chemoresistance, prompting research into its drivers.
- AXL receptor tyrosine kinase is crucial for resistance to therapies in mesenchymal cancer cells, but its induction mechanism is unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying AXL expression in mesenchymal-type lung cancer.
- To identify potential therapeutic targets for overcoming chemoresistance in lung cancer.
Main Methods:
- Analysis of YAP signature correlation with AXL expression in 181 lung cancer cell lines.
- Experiments using isogenic lung cancer cell pairs to study doxorubicin's effect on YAP and AXL.
- Investigation of TGFβ signaling and SMAD4 involvement in YAP-dependent AXL induction.
Main Results:
- A strong correlation was found between the YAP signature and AXL expression in mesenchymal-type lung cancer.
- Doxorubicin treatment induced YAP nuclear translocation, leading to increased AXL expression in mesenchymal lung cancer cells.
- TGFβ signaling activation, coordinated by SMAD4, contributed to YAP-dependent AXL expression.
Conclusions:
- Crosstalk between YAP and the TGFβ/SMAD axis is implicated in AXL induction upon chemotherapy.
- Targeting the YAP and TGFβ/SMAD pathway interaction may enhance chemosensitivity in mesenchymal-type lung cancer.
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