COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis.
Yu Zheng, Valentine Comaills, Risa Burr, Gaylor Boulay, David T Miyamoto, Ben S Wittner, Erin Emmons, Srinjoy Sil, Michael W Koulopoulos, Katherine T Broderick, Eric Tai, Shruthi Rengarajan, Anupriya S Kulkarni, Toshi Shioda, Chin-Lee Wu, Sridhar Ramaswamy, David T Ting, Mehmet Toner, Miguel N Rivera, Shyamala Maheswaran, Daniel A Haber
Author Information
Yu Zheng: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Valentine Comaills: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Risa Burr: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Gaylor Boulay: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
David T Miyamoto: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Ben S Wittner: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Erin Emmons: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Srinjoy Sil: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Michael W Koulopoulos: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Katherine T Broderick: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Eric Tai: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Shruthi Rengarajan: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Anupriya S Kulkarni: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Toshi Shioda: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Chin-Lee Wu: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Sridhar Ramaswamy: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
David T Ting: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Mehmet Toner: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Miguel N Rivera: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Shyamala Maheswaran: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Daniel A Haber: Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129; dhaber@mgh.harvard.edu.
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.
