Author:
Zheng Yu,Comaills Valentine,Burr Risa,Boulay Gaylor,Miyamoto David T.,Wittner Ben S.,Emmons Erin,Sil Srinjoy,Koulopoulos Michael W.,Broderick Katherine T.,Tai Eric,Rengarajan Shruthi,Kulkarni Anupriya S.,Shioda Toshi,Wu Chin-Lee,Ramaswamy Sridhar,Ting David T.,Toner Mehmet,Rivera Miguel N.,Maheswaran Shyamala,Haber Daniel A.
Abstract
Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.
Funder
HHS | NIH | National Institute of Biomedical Imaging and Bioengineering
HHS | NIH | National Cancer Institute
Publisher
Proceedings of the National Academy of Sciences
Cited by
32 articles.
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