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The Inhibition of Wnt Restrain KRASG12V-Driven Metastasis in Non-Small-Cell Lung Cancer
Pei-Shan Hung1, Ming-Hung Huang1, Yuan-Yeh Kuo2
1Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Abstract:
The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRASG12V/KRASG12D mutations and inhibited the KRASG12V mediated metastasis by Wnt inhibitor. First, we found that KRASG12V induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRASG12V cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRASG12D induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838KRASG12D cells. The restored activation of Wnt/β-catenin in H838KRASG12D cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRASG12V-induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRASG12V driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRASG12V/KRASG12D is distinct.
Insights
KRAS mutations drive distinct non-small-cell lung carcinoma (NSCLC) metastasis patterns. Researchers found KRAS G12V-induced metastasis is Wnt-dependent, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- KRAS mutations are significant drivers in non-small-cell lung carcinoma (NSCLC).
- Identifying distinct therapeutic targets for KRAS-mutated NSCLC remains a challenge.
- Understanding the mechanisms of metastasis in NSCLC is crucial for effective treatment.
Purpose of the Study:
- To elucidate the distinct metastasis patterns induced by KRAS G12V and KRAS G12D mutations in NSCLC.
- To investigate the role of RhoA and Wnt/β-catenin signaling in KRAS-driven NSCLC metastasis.
- To evaluate the potential of Wnt inhibitors in targeting KRAS G12V-mediated metastasis.
Main Methods:
- In vitro and in vivo experiments to assess cancer cell phenotypes.
- Gene Set Enrichment Analysis (GSEA) to identify signaling pathway correlations.
- Manipulation of RhoA signaling using dominant-negative mutants and inhibitors.
- Treatment with Wnt inhibitors to block metastasis.
Main Results:
- KRAS G12V induced a more aggressive phenotype compared to KRAS G12D.
- KRAS G12V showed a negative correlation with RhoA signaling, while KRAS G12D showed increased RhoA activation and suppressed Wnt/β-catenin.
- Restoration of Wnt/β-catenin signaling was achieved by inhibiting RhoA.
- Wnt inhibition effectively abolished KRAS G12V-induced cell migration.
Conclusions:
- The RhoA/Wnt axis plays a critical role in regulating NSCLC metastasis driven by KRAS mutations.
- KRAS G12V-driven NSCLC metastasis is dependent on Wnt signaling.
- Distinct molecular mechanisms underlie NSCLC metastasis induced by KRAS G12V and KRAS G12D mutations, highlighting specific therapeutic vulnerabilities.
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