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

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 3

Roles of membranous KRS in the disseminative outgrowths from 3D spheroids.

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Roles of membranous KRS in the disseminative outgrowths from 3D spheroid...
(A) KRS-suppressed colon cancer spheroids (shKRS#2) were treated with M2 macrophage-CM for 2 days (2d:00h:00min) in the absence or presence of antibodies against FGFR, GROα, or M-CSF and were time-lapse-imaged. (B) Cells were embedded in 3D collagen I gels with normal media or M2 macrophage-CM. In addition, the 3D culture medium was treated with normal IgG (Nor IgG) or antibodies to neutralize human α6 integrin, p67LR, or both, before time-lapse imaging for 1 day and 18 hours (1d:18h:00min). (C and D) KRS-positive spheroids (shControl) were treated with normal IgG or antibodies against αvβ3 integrin (C) or membranous KRS (KRSmem; D) with or without concomitant treatment of M2 macrophage-CM. The disseminative phenotypes (shown in A) for each experimental condition are also presented in graphs as percentage values (A, C, and D). The data shown represent 3 independent experiments. See also Supplemental Figure 4. Scale bars: 40 μm.