Contact

  • Academic
    songnanw@stanford.edu
    University - Student Department: Biochemistry Position: Graduate
    University - Student Department: School of Medicine Position: Graduate, Medicine

Additional Info

  • Mail Code: 5151

All Publications

  • ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway in breast cancer. Proceedings of the National Academy of Sciences of the United States of America Wang, S., Böhnert, V., Joseph, A. J., Sudaryo, V., Skariah, G., Swinderman, J. T., Yu, F. B., Subramanyam, V., Wolf, D. M., Lyu, X., Gilbert, L. A., Van't Veer, L. J., Goodarzi, H., Li, L. 2023; 120 (52): e2313693120

    Abstract

    Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 2'3'-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer.

    View details for DOI 10.1073/pnas.2313693120

    View details for PubMedID 38117852

  • ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway. bioRxiv : the preprint server for biology Wang, S., Böhnert, V., Joseph, A. J., Sudaryo, V., Swinderman, J., Yu, F. B., Lyu, X., Skariah, G., Subramanyam, V., Gilbert, L. A., Goodarzi, H., Lingyin, L. 2023

    Abstract

    ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary breast tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling. In addition to cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 that restrains their response to tumor-derived cGAMP. Enpp1 loss-of-function in both cancer cells and normal tissues slowed primary tumor initiation and growth and prevented metastasis in an extracellular cGAMP- and STING-dependent manner. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Strikingly, we find that breast cancer patients with low ENPP1 expression have significantly higher immune infiltration and improved response to therapeutics impacting cancer immunity upstream or downstream of the cGAMP-STING pathway, like PARP inhibitors and anti-PD1. Altogether, selective inhibition of ENPP1's cGAMP hydrolase activity alleviates an innate immune checkpoint to boost cancer immunity and is therefore a promising therapeutic approach against breast cancer that may synergize with other cancer immunotherapies.

    View details for DOI 10.1101/2023.06.01.543353

    View details for PubMedID 37333273

    View details for PubMedCentralID PMC10274658