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, I. Szatmári, Massimiliano Mazzone, L. Nagy

Research output: Contribution to journalArticle

5 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

Fingerprint

Retinoid X Receptors
Myeloid Cells
Neoplasm Metastasis
Ligands
Nuclear Receptor Co-Repressor 2
Neoplasms
Co-Repressor Proteins
Lung
Cytoplasmic and Nuclear Receptors
Phagocytosis
Chemokines
Cell Movement
Lung Neoplasms
Blood Cells
Lipids
Gene Expression
Growth

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism. / Kiss, Mate; Czimmerer, Zsolt; Nagy, Gergely; Bieniasz-Krzywiec, Pawel; Ehling, Manuel; Pap, Attila; Poliska, Szilard; Boto, Pal; Tzerpos, Petros; Horvath, Attila; Kolostyak, Zsuzsanna; Daniel, Bence; Szatmári, I.; Mazzone, Massimiliano; Nagy, L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 40, 03.10.2017, p. 10725-10730.

Research output: Contribution to journalArticle

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, Szatmári, 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, vol. 114, no. 40, pp. 10725-10730. https://doi.org/10.1073/pnas.1700785114
Kiss, Mate ; Czimmerer, Zsolt ; Nagy, Gergely ; Bieniasz-Krzywiec, Pawel ; Ehling, Manuel ; Pap, Attila ; Poliska, Szilard ; Boto, Pal ; Tzerpos, Petros ; Horvath, Attila ; Kolostyak, Zsuzsanna ; Daniel, Bence ; Szatmári, I. ; Mazzone, Massimiliano ; Nagy, L. / Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 40. pp. 10725-10730.
@article{4b713dfce4864a7ab40c6279c9f015a8,
title = "Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism",
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.",
keywords = "Metastasis, Myeloid cell, NCoR, Premetastatic niche, Retinoid X receptor",
author = "Mate Kiss and Zsolt Czimmerer and Gergely Nagy and Pawel Bieniasz-Krzywiec and Manuel Ehling and Attila Pap and Szilard Poliska and Pal Boto and Petros Tzerpos and Attila Horvath and Zsuzsanna Kolostyak and Bence Daniel and I. Szatm{\'a}ri and Massimiliano Mazzone and L. Nagy",
year = "2017",
month = "10",
day = "3",
doi = "10.1073/pnas.1700785114",
language = "English",
volume = "114",
pages = "10725--10730",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "40",

}

TY - JOUR

T1 - Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

AU - Kiss, Mate

AU - Czimmerer, Zsolt

AU - Nagy, Gergely

AU - Bieniasz-Krzywiec, Pawel

AU - Ehling, Manuel

AU - Pap, Attila

AU - Poliska, Szilard

AU - Boto, Pal

AU - Tzerpos, Petros

AU - Horvath, Attila

AU - Kolostyak, Zsuzsanna

AU - Daniel, Bence

AU - Szatmári, I.

AU - Mazzone, Massimiliano

AU - Nagy, L.

PY - 2017/10/3

Y1 - 2017/10/3

N2 - 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.

AB - 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.

KW - Metastasis

KW - Myeloid cell

KW - NCoR

KW - Premetastatic niche

KW - Retinoid X receptor

UR - http://www.scopus.com/inward/record.url?scp=85030473268&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030473268&partnerID=8YFLogxK

U2 - 10.1073/pnas.1700785114

DO - 10.1073/pnas.1700785114

M3 - Article

C2 - 28923935

AN - SCOPUS:85030473268

VL - 114

SP - 10725

EP - 10730

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 40

ER -