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Inducible TgfbR1 and Pten deletion in a model of tongue carcinogenesis and chemoprevention

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is a significant public health problem, with a need for novel approaches to chemoprevention and treatment. Preclinical models that recapitulate molecular alterations that occur in clinical HNSCC patients are needed to better understand molecular and immune mechanisms of HNSCC carcinogenesis, chemoprevention, and efficacy of treatment. We optimized a mouse model of tongue carcinogenesis with discrete quantifiable tumors via conditional deletion of Tgfβr1 and Pten by intralingual injection of tamoxifen. We characterized the localized immune tumor microenvironment, metastasis, systemic immune responses, associated with tongue tumor development. We further determined the efficacy of tongue cancer chemoprevention using dietary administration of black raspberries (BRB). Three Intralingual injections of 500 µg tamoxifen to transgenic K14 Cre, floxed Tgfbr1, Pten (2cKO) knockout mice resulted in tongue tumors with histological and molecular profiles, and lymph node metastasis similar to clinical HNSCC tumors. Bcl2, Bcl-xl, Egfr, Ki-67, and Mmp9, were significantly upregulated in tongue tumors compared to surrounding epithelial tissue. CD4+ and CD8 + T cells in tumor-draining lymph nodes and tumors displayed increased surface CTLA-4 expression, suggestive of impaired T-cell activation and enhanced regulatory T-cell activity. BRB administration resulted in reduced tumor growth, enhanced T-cell infiltration to the tongue tumor microenvironment and robust antitumoral CD8+ cytotoxic T-cell activity characterized by greater granzyme B and perforin expression. Our results demonstrate that intralingual injection of tamoxifen in Tgfβr1/Pten 2cKO mice results in discrete quantifiable tumors suitable for chemoprevention and therapy of experimental HNSCC.

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Fig. 1: Characterization of tamoxifen-injected inducible PTEN and TGFβ-R1 knockout mouse.
Fig. 2: Optimization of injection protocol for induction of HNSCC in Tgfβr1/Pten 2cKO mice.
Fig. 3: Molecular characterization of HNSCC tumor development, progression, and metastasis in Tgfβr1/Pten 2cKO mice.
Fig. 4: Lymphoid cell populations in HNSCC tumor-bearing Tgfβr1/Pten 2cKO mice.
Fig. 5: Cytokine, Perforin and Granzyme B production in lymphoid cell populations in HNSCC tumor-bearing Tgfβr1/Pten 2cKO mice.
Fig. 6: Black raspberry diet reduces HNSCC tumor burdens of mice with PTEN and TGFβ-R1 deletion.
Fig. 7: Dietary BRB administration promotes T-cell infiltration to the tumor microenvironment.
Fig. 8: Dietary BRB administration stimulates antitumoral CD8+ cytotoxic T-cell activity in HNSCC induced Tgfβr1/Pten 2cKO mice.

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Data availability

All data needed to evaluate the conclusions in this paper are present in the article and/or supplementary information. Additional data related to this paper are available from the corresponding author upon reasonable request.

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Funding

This work was funded by the National Institutes of Health grants K01CA207599 (NCI/NIH), R56DE030093 (NIDCR/NIH), and DP1DA054344 (NIDA/NIH), as well as the American Cancer Society (ACS), grant RSG-19079-01-TBG awarded to SO.

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Authors and Affiliations

  1. Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Felipe F. Lamenza, Nathan M. Ryan, Puja Upadhaya, Arham Siddiqui, Pete P. Jordanides, Anna Springer, Peyton Roth, Hasan Pracha, O. Hans Iwenofu & Steve Oghumu

  2. Department of Microbiology, The Ohio State University, Columbus, OH, USA

    Felipe F. Lamenza

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  1. Felipe F. Lamenza
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Contributions

FL, NR, PU, AS, PJ, AS, PR and HP performed the experiments and data analysis. OHI contributed to histopathological analysis. FL and SO drafted the manuscript and revised. SO initiated and supervised the entire study. All authors reviewed and approved the final manuscript.

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Correspondence to Steve Oghumu.

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Lamenza, F.F., Ryan, N.M., Upadhaya, P. et al. Inducible TgfbR1 and Pten deletion in a model of tongue carcinogenesis and chemoprevention. Cancer Gene Ther 30, 1167–1177 (2023). https://doi.org/10.1038/s41417-023-00629-8

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