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MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types

Oncogene volume 38, pages 7384–7398 (2019)Cite this article

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Abstract

Protease-activated receptor 1 (PAR1), a thrombin-responsive G protein-coupled receptor (GPCR), is implicated in promoting metastasis in multiple tumor types, including both sarcomas and carcinomas, but the molecular mechanisms responsible remain largely unknown. We previously discovered that PAR1 stimulation in endothelial cells leads to activation of NF-κB, mediated by a protein complex comprised of CARMA3, Bcl10, and the MALT1 effector protein (CBM complex). Given the strong association between NF-κB and metastasis, we hypothesized that this CBM complex could play a critical role in the PAR1-driven metastatic progression of specific solid tumors. In support of our hypothesis, we demonstrate that PAR1 stimulation results in NF-κB activation in both osteosarcoma and breast cancer, which is suppressed by siRNA-mediated MALT1 knockdown, suggesting that an intact CBM complex is required for the response in both tumor cell types. We identify several metastasis-associated genes that are upregulated in a MALT1-dependent manner after PAR1 stimulation in cancer cells, including those encoding the matrix remodeling protein, MMP9, and the cytokines, IL-1β and IL-8. Further, exogenous expression of PAR1 in MCF7 breast cancer cells confers highly invasive and metastatic behavior which can be blocked by CRISPR/Cas9-mediated MALT1 knockout. Importantly, we find that PAR1 stimulation induces MALT1 protease activity in both osteosarcoma and breast cancer cells, an activity that is mechanistically linked to NF-κB activation and potentially other responses associated with aggressive phenotype. Several small molecule MALT1 protease inhibitors have recently been described that could therefore represent promising new therapeutics for the prevention and/or treatment of PAR1-driven tumor metastasis.

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Acknowledgements

The authors wish to thank Celia Paris for her support and Katrina O’Halloran, Emily Elliott, Yijen Wu, Amir Borhani, and Nathan Salamacha for their technical assistance. In addition, we thank Dr Ed Prochownik for use of his laboratory equipment. This work was supported by NIH Grant 5F30CA196095 to JRM and a Hyundai Scholar’s Hope Grant #91499PA to LMM-L. JRM also received support from The University of Pittsburgh Medical Scientist Training Program (MSTP) T32GM008208. KMB received support from an NIH career development award, K12HD052892, an Alex’s Lemonade Stand Foundation Young Investigator Award, and the John G. Rangos Senior Research Scholar Fund.

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  1. These authors contributed equally: Peter C. Lucas, Linda M. McAllister-Lucas

Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J. Randall McAuley, Linda R. Klei, Heejae Kang, Dong Hu, Tanner J. Freeman, Nathaniel E. Hubel, Jia-Ying (Lloyd) Lee & Peter C. Lucas

  2. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Kelly M. Bailey, Prasanna Ekambaram, Vincent J. Concel, Nathaniel E. Hubel, Hanna B. Klei, Jing Cheng, Preethiya Sekar, Rachel E. Bridwell, Peter C. Lucas & Linda M. McAllister-Lucas

  3. Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA

    Lidija Covic

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McAuley, J.R., Bailey, K.M., Ekambaram, P. et al. MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types. Oncogene 38, 7384–7398 (2019). https://doi.org/10.1038/s41388-019-0958-4

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