Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

Mate Kiss, Zsolt Czimmerer, Gergely Nagy, Pawel Bieniasz-Krzywiec, Manuel Ehling, Attila Pap, Szilard Poliska, Pal Boto, Petros Tzerpos, Attila Horvath, Zsuzsanna Kolostyak, Bence Daniel, Istvan Szatmari, Massimiliano Mazzone, Laszlo Nagy

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Retinoid X receptor (RXR) regulates several key functions in myeloid cells, including inflammatory responses, phagocytosis, chemokine secretion, and proangiogenic activity. Its importance, however, in tumor-associated myeloid cells is unknown. In this study, we demonstrate that deletion of RXR in myeloid cells enhances lung metastasis formation while not affecting primary tumor growth. We show that RXR deficiency leads to transcriptomic changes in the lung myeloid compartment characterized by increased expression of prometastatic genes, including important determinants of premetastatic niche formation. Accordingly, RXR-deficient myeloid cells are more efficient in promoting cancer cell migration and invasion. Our results suggest that the repressive activity of RXR on prometastatic genes is mediated primarily through direct DNA binding of the receptor along with nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors and is largely unresponsive to ligand activation. In addition, we found that expression and transcriptional activity of RXRα is down-modulated in peripheral blood mononuclear cells of patients with lung cancer, particularly in advanced and metastatic disease. Overall, our results identify RXR as a regulator in the myeloid cell-assisted metastatic process and establish lipid-sensing nuclear receptors in the microenvironmental regulation of tumor progression.

Original languageEnglish
Pages (from-to)10725-10730
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number40
DOIs
Publication statusPublished - Oct 3 2017

Keywords

  • Metastasis
  • Myeloid cell
  • NCoR
  • Premetastatic niche
  • Retinoid X receptor

ASJC Scopus subject areas

  • General

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    Kiss, M., Czimmerer, Z., Nagy, G., Bieniasz-Krzywiec, P., Ehling, M., Pap, A., Poliska, S., Boto, P., Tzerpos, P., Horvath, A., Kolostyak, Z., Daniel, B., Szatmari, I., Mazzone, M., & Nagy, L. (2017). Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism. Proceedings of the National Academy of Sciences of the United States of America, 114(40), 10725-10730. https://doi.org/10.1073/pnas.1700785114