Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 11, Pages 5034-5055Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI99806
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Funding
- Basic Science Research Program through the National Research Foundation of Korea - Ministry of Science, ICT and Future Planning [NRF-2018M3A9C8020027, NRF-2017R1A2B3005015]
- Tumor Microenvironment Globarl Core Research Center [2011-0030001]
- Medicinal Bioconvergence Research Center [NRF-2013M3A6A4044019]
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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/GRO alpha/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.
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