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

Proceedings of the National Academy of Sciences of the United States of America
Yu ZhengDaniel A Haber

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.

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Citations

Mar 13, 2019·Proceedings of the National Academy of Sciences of the United States of America·Beth Azar
May 30, 2020·Seminars in Cancer Biology·Haseeb ZubairAjay Pratap Singh
Oct 28, 2020·Molecular Cancer Research : MCR·Stephen Safe, Keshav Karki
Feb 5, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Lan WangYongqian Xu
Feb 27, 2021·Frontiers in Cell and Developmental Biology·Daniel Crean, Evelyn P Murphy
Oct 29, 2020·Seminars in Cell & Developmental Biology·Ödül Karayazi AtıcıCarrie S Shemanko
Sep 1, 2021·European Journal of Pharmacology·Qi-Zhang LiYan Ji

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Datasets Mentioned

BETA
GSE96676

Methods Mentioned

BETA
RNA-Seq
dissect
ELISA
immunoprecipitation
ChIP-Seq
surgical resection
dissection

Software Mentioned

Biocarta

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