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J Clin Invest. 2018 Nov 1;128(11):5034-5055. doi: 10.1172/JCI99806. Epub 2018 Oct 8.

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

Author information

1
Interdisciplinary Program in Genetic Engineering.
2
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, and.
3
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Republic of Korea.
4
Department of Microbiology, Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
5
Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do, Republic of Korea.

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.

KEYWORDS:

Cancer; Cell migration/adhesion; Gastroenterology; Macrophages; Oncology

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