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Publications

Journal Article Ppublish 27 citations

PubMed: 38117852 DOI: 10.1073/pnas.2313693120

ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway in breast cancer.

Proc Natl Acad Sci U S A 120(52):e2313693120

Authors: Songnan Wang, Volker Böhnert, Alby J Joseph, Valentino Sudaryo, Gemini Skariah, Jason T Swinderman, Feiqiao B Yu, Vishvak Subramanyam, Denise M Wolf, Xuchao Lyu, Luke A Gilbert, Laura J Van't Veer, Hani Goodarzi, Lingyin Li

Affiliations

  • Department of Biochemistry, Stanford University, Stanford, CA 94305.
  • ChEM-H Institute, Stanford University, Stanford, CA 94305.
  • Arc Institute, Palo Alto, CA 94304.
  • Department of Biochemistry, Stanford University, Stanford, CA 94305. ChEM-H Institute, Stanford University, Stanford, CA 94305. Arc Institute, Palo Alto, CA 94304.
  • Department of Urology, University of California, San Francisco, CA 94143.
  • Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
  • Department of Biophysics & Biochemistry, University of California, San Francisco, CA 94143.
  • Baker Computational Health Science Institute, University of California, San Francisco, CA 94143.
  • Department of Laboratory Medicine, University of California, San Francisco, CA 94115.
  • Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.

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, 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.

MeSH

Growth, Neoplasm Metastasis, Cells, Therapeutics, Breast Neoplasms, Tissues

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