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Lysyl-tRNA synthetase–expressing colon spheroids induce M2 macrophage polarization to promote metastasis
Seo Hee Nam, … , Sunghoon Kim, Jung Weon Lee
Seo Hee Nam, … , Sunghoon Kim, Jung Weon Lee
Published September 6, 2018
Citation Information: J Clin Invest. 2018;128(11):5034-5055. https://doi.org/10.1172/JCI99806.
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Research Article Gastroenterology Oncology

Lysyl-tRNA synthetase–expressing colon spheroids induce M2 macrophage polarization to promote metastasis

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Abstract

Lysyl-tRNA synthetase (KRS) functions canonically in cytosolic translational processes. However, KRS is highly expressed in colon cancer, and localizes to distinct cellular compartments upon phosphorylations (i.e., the plasma membranes after T52 phosphorylation and the nucleus after S207 phosphorylation), leading to probably alternative noncanonical functions. It is unknown how other subcellular KRSs crosstalk with environmental cues during cancer progression. Here, we demonstrate that the KRS-dependent metastatic behavior of colon cancer spheroids within 3D gels requires communication between cellular molecules and extracellular soluble factors and neighboring cells. Membranous KRS and nuclear KRS were found to participate in invasive cell dissemination of colon cancer spheroids in 3D gels. Cancer spheroids secreted GAS6 via a KRS-dependent mechanism and caused the M2 polarization of macrophages, which activated the neighboring cells via secretion of FGF2/GROα/M-CSF to promote cancer dissemination under environmental remodeling via fibroblast-mediated laminin production. Analyses of tissues from clinical colon cancer patients and Krs–/+ animal models for cancer metastasis supported the roles of KRS, GAS6, and M2 macrophages in KRS-dependent positive feedback between tumors and environmental factors. Altogether, KRS in colon cancer cells remodels the microenvironment to promote metastasis, which can thus be therapeutically targeted at these bidirectional KRS-dependent communications of cancer spheroids with environmental cues.

Authors

Seo Hee Nam, Doyeun Kim, Doohyung Lee, Hye-Mi Lee, Dae-Geun Song, Jae Woo Jung, Ji Eon Kim, Hye-Jin Kim, Nam Hoon Kwon, Eun-Kyeong Jo, Sunghoon Kim, Jung Weon Lee

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Figure 4

Nuclear KRS in colon cancer spheroids increases GAS6 expression for the M2 polarization of macrophages.

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Nuclear KRS in colon cancer spheroids increases GAS6 expression for the ...
(A) The relative mRNA levels of IL6, IL10, or CD206 in THP-1 macrophages were analyzed after treatment with CM of HCT116 KRS-positive (shControl or KRS-WT) or KRS-suppressed (shKRS#2) colon cancer spheroids for 24 hours. The data are presented as the mean ± SD. (B) GAS6, IL8, and other cytokine mRNA levels were analyzed in the 3D spheroids with different KRS expression levels for 24 hours. (C and D) THP-1 monocytes, M1 macrophages, or M2 macrophages were treated with GAS6, IL-8, and/or ANG, before measurement of the levels of CD206 (C) and IL10 (D) mRNA. (E and F) THP-1 M1 macrophages or M2 macrophages were treated with CM (E and F) or GAS6, IL-8, and/or ANG (F) for 24 hours before analysis of the protein levels of TNF-α, IL-10, or arginase by ELISA. The data shown represent 3 different observations. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Dunnett tests. See also Supplemental Figures 4 and 5.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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