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Oncogenic BRAF noncanonically promotes tumor metastasis by mediating VASP phosphorylation and filopodia formation

Oncogene volume 42, pages 3194–3205 (2023)Cite this article

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Abstract

BRAF is frequently mutated in various cancer types and contributes to tumorigenesis and metastasis. As an important switch in RAS signaling pathway, BRAF typically enables the activation of MEK and ERK, and its mutation significantly promotes metastasis. However, whether BRAF could stimulate metastasis via a distinct manner is still unknown. Herein, we found that a portion of the BRAF protein localized at the plasma membrane and that the BRAFV600E mutation led to abundant formation of filopodia, which is a hallmark of invasive cancer cells. Mechanistically, BRAF physically interacts with the pseudopod formation-related protein Vasodilator-stimulated phosphoprotein (VASP), and BRAF specifically catalyzes VASP phosphorylation at Ser157. VASP depletion or disruption of Ser157 phosphorylation preferentially reduced the motility, invasion and metastasis of tumor cells harboring oncogenic BRAF or KRAS. Moreover, in clinical cancer tissues, BRAFV600E was positively correlated with the extent of invasion, and tissues with BRAFV600E expression exhibited elevated levels of VASP Ser157 phosphorylation. Our study therefor reveals a noncanonical mechanism by which oncogenic BRAF or KRAS promotes metastasis, suggests that VASP Ser157 phosphorylation might serve as a valuable therapeutic target in BRAF or KRAS mutant cancers.

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Fig. 1: Subcellular localization of BRAF and its effect on cell migration.
Fig. 2: BRAF physically interacts with VASP.
Fig. 3: BRAFV600E phosphorylates VASP at Ser157.
Fig. 4: The effect of VASP on the migration of tumor cells expressing oncogenic KRAS or BRAF.
Fig. 5: Effect of VASP and VASP-S157P on tumor cell filopodia formation.
Fig. 6: VASP expression and Ser157 phosphorylation affect the metastasis of BRAFV600E-positive tumors.
Fig. 7: Correlation between clinicopathological features of patients with the BRAFV600E mutation and the VASP or VASP-S157P level.

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All data generated or analyzed during this study are included in this article and its Supplementary Information Files.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant numbers 82373047, 82173137, 82203491 and 82072950), the Natural Science Foundation of Hubei Province of China (grant number 2022CFA008). the Fundamental research Funds for the Central Universities (grant number 2042022kf1212 and 2042022kf1209), the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (grant number NJC202212) and the Medical Science Advancement Program (Basic Medical Science) of Wuhan University (grant number TFJC2018003).

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Authors and Affiliations

  1. Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China

    Wenting Pan, Zelin Yang & Lei Wei

  2. Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, China

    Yihao Tian

  3. Department of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan, China

    Qian Zheng, Yulong Qiang, Nan Zhang & Feng Li

  4. Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Zun Zhang

  5. Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China

    Jie Xiong

  6. Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China

    Xin Zhu

  7. Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China

    Lei Wei

  8. Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan, China

    Feng Li

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Contributions

FL conceived and designed the study. FL, WP and LW contributed to the literature search. WP, YT, ZY and QZ performed the experiments. XZ collected tumor samples and provided patient metadata. WP, JX and XZ performed analyses of the clinical metadata. WP, FL, LW and YT contributed to data analysis. FL, WP and YQ contributed to data interpretation. WP, ZZ, NZ and FL contributed to the figures. FL and WP contributed to the writing of the manuscript.

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Correspondence to Jie Xiong, Xin Zhu, Lei Wei or Feng Li.

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Pan, W., Tian, Y., Zheng, Q. et al. Oncogenic BRAF noncanonically promotes tumor metastasis by mediating VASP phosphorylation and filopodia formation. Oncogene 42, 3194–3205 (2023). https://doi.org/10.1038/s41388-023-02829-w

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