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Targeted deactivation of cancer-associated fibroblasts by β-catenin ablation suppresses melanoma growth

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Tumor Biology

Abstract

Cancer-associated fibroblasts (CAFs) are the crucial components of the dynamic tumor microenvironment, which not only supports the growth and metastasis of melanoma but also contributes to drug resistance in melanoma treatment. We recently discovered that loss of β-catenin signaling deactivated stromal fibroblasts and reduced the production of paracrine factors and extracellular matrix proteins. Based on this finding, we aimed to determine whether melanoma growth could be suppressed by targeted deactivation of CAFs via β-catenin ablation using a combination of in vitro and in vivo approaches. Using an in vitro three-dimensional (3D) tumor co-culture model, we showed that β-catenin-deficient fibroblasts lost the ability to respond to melanoma cell stimulation and to support the growth of B16F10 melanoma cells. To determine the in vivo effects of CAF deactivation on melanoma growth, we designed a novel genetic approach to ablate β-catenin expression in melanoma-associated fibroblasts only after melanoma tumor was formed. As expected, our observation showed that development of B16F10 melanoma was significantly delayed when β-catenin expression was ablated in CAFs. We determined that inhibition of tumor growth was due to decreased melanoma cell proliferation and increased cell death. Further analysis revealed that CAF deactivation caused the downregulation of the MAPK/ERK signaling cascade and S and G2/M phase cell cycle arrest in B16F10 melanoma cells. Overall, our data emphasize the significance of targeting CAFs as a potential novel therapeutic approach to improve melanoma treatment by creating a tumor-suppressive microenvironment through tumor-stroma interactions.

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Acknowledgments

We thank Dr. Benoit de Crombrugghe for the Col1α2-CreER mice.

Funding

This work was supported by the Elsa U. Pardee Foundation, University of Cincinnati-MRA Young Investigator Award (grant number 300586), the Cincinnati Cancer Center—Mentor-Mentee Award, the Skin Cancer Foundation—The Dr. Marcia Robbins-Wilf Research Grant Award, and the Harry J. LIoyd Trust Research Award.

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA

    Linli Zhou, Kun Yang, R. Randall Wickett & Yuhang Zhang

  2. Department of Dermatology, College of Medicine University of Cincinnati, Cincinnati, OH, 45267, USA

    Ana Luisa Kadekaro

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  1. Linli Zhou
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Correspondence to Yuhang Zhang.

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Zhou, L., Yang, K., Wickett, R.R. et al. Targeted deactivation of cancer-associated fibroblasts by β-catenin ablation suppresses melanoma growth. Tumor Biol. 37, 14235–14248 (2016). https://doi.org/10.1007/s13277-016-5293-6

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