COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis.

摘要: 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 prolactin receptor as cells that have disseminated lungs expand into micrometastases. Secretion ligand by adjacent lung stromal is induced tumor cell production COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment fibroblasts activates orphan nuclear NR4A (Nur77), with major transcriptional target for NR4A-retinoid X (RXR) heterodimer. Ectopic expression enhances micrometastasis, while inhibitor celecoxib abrogates secretion reduces initiation. Across multiple human cancers, COX-2, prolactin, show consistent differential compartments. Such paracrine cross-talk thus contribute documented efficacy inhibitors suppression.