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Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFβ signaling

Oncogene volume 35, pages 4641–4652 (2016)Cite this article

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Abstract

Head and neck squamous cell carcinoma (HNSCC) patients have a poor prognosis, with invasion and metastasis as major causes of mortality. The phosphatidylinositol 3-kinase (PI3K) pathway regulates a wide range of cellular processes crucial for tumorigenesis, and PIK3CA amplification and mutation are among the most common genetic alterations in human HNSCC. Compared with the well-documented roles of the PI3K pathway in cell growth and survival, the roles of the PI3K pathway in tumor invasion and metastasis have not been well delineated. We generated a PIK3CA genetically engineered mouse model (PIK3CA-GEMM) in which wild-type PIK3CA is overexpressed in head and neck epithelium. Although PIK3CA overexpression alone was not sufficient to initiate HNSCC formation, it significantly increased tumor susceptibility in an oral carcinogenesis mouse model. PIK3CA overexpression in mouse oral epithelium increased tumor invasiveness and metastasis by increasing epithelial–mesenchymal transition and by enriching a cancer stem cell phenotype in tumor epithelial cells. In addition to these epithelial alterations, we also observed marked inflammation in tumor stroma. AKT is a central signaling mediator of the PI3K pathway. However, molecular analysis suggested that progression of PIK3CA-driven HNSCC is facilitated by 3-phosphoinositide-dependent protein kinase (PDK1) and enhanced transforming growth factor β (TGFβ) signaling rather than by AKT. Examination of human HNSCC clinical samples revealed that both PIK3CA and PDK1 protein levels correlated with tumor progression, highlighting the significance of this pathway. In summary, our results offer significant insight into how PIK3CA overexpression drives HNSCC invasion and metastasis, providing a rationale for targeting PI3K/PDK1 and TGFβ signaling in advanced HNSCC patients with PIK3CA amplification.

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Acknowledgements

This work is supported by National Institutes of Health grant R01DE021788 (to S-L Lu), R01DE015953 (to X-J Wang). University of Colorado Academic Enrichment Fund (to S-L Lu), American Cancer Society (to S-L Lu), University of Colorado Cancer Center (to S-L Lu), and Cancer League of Colorado (to S-L Lu). S-L Lu is an investigator of THANC foundation. We thank the Transgenic Core of Oregon Health and Science University for generating founders of the mouse model, and the University of Colorado Skin Disease Research Center Morphology Phenotyping Core (P30 AR057212) for assisting with histological work.

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  1. L Du and X Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Otolaryngology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    L Du, X Chen, Y Cao, L Lu, F Zhang & S-L Lu

  2. Department of Otolaryngology, Fourth University Hospital of China Medical University, Shengyang, China

    L Du

  3. Department of Surgical Oncology, The First University Hospital of China Medical University, Shengyang, Liaoning, China

    Y Cao & F Jin

  4. Department of Otolaryngology, Oregon Health and Science University, Portland, OR, USA

    S Bornstein, Y Li, P Owens & N Gross

  5. Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    S Malkoski

  6. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    S Said, X-J Wang & S-L Lu

  7. Department of Dermatology, Oregon Health and Science University, Portland, OR, USA

    M Kulesz-Martin

  8. Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    S-L Lu

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  1. L Du
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Du, L., Chen, X., Cao, Y. et al. Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFβ signaling. Oncogene 35, 4641–4652 (2016). https://doi.org/10.1038/onc.2016.1

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