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.

Plasma Lysyl-tRNA Synthetase 1 (KARS1) as a Novel Diagnostic and Monitoring Biomarker for Colorectal Cancer

“…These findings show that KARS1 is secreted into the blood from the tumors of CRC patients, and are consistent with our previous report that KARS1 is secreted from colon cancer cell lines. Since plasma KARS1 is highly correlated to primary tumor size of CRC patients and secreted KARS1 induces macrophage M2 polarization [24], it can be attributed to CRC tumorigenesis and metastasis, perhaps functionally associated with its macrophage M2 activity [44,45]. However, more mechanistic and clinical studies are needed to validate the etiological contribution of plasma KARS1 to CRC.…”

“…Whereas membrane KARS1 has been found to regulate tumor migration, secreted KARS1 exhibits proinflammatory functions in the cancer microenvironment [22,23]. The overexpressed membrane-bound KARS1 induces tumor cell migration for the progression of colon cancer [24]. KARS1 is normally anchored to the multi-synthetase complex (MSC) in the cytosol but released from MSC through caspase 8-mediated N-terminal truncation.…”

“…Although the secretory pathway and function of KARS1 have been reported, its clinical relevance has not been validated yet. Overexpressed membrane-bound KARS1 and secreted KARS1 induce tumor cell migration and tumorigenic inflammation, respectively, for colon cancer progression [24]. Based on this, we analyzed the plasma levels of KARS1 in human CRC samples and in a colitis-induced CRC mouse model.…”

The tRNA‐associated dysregulation in immune responses and immune diseases

“…Colon cancer spheroids secreted growth arrestspecific 6 (GAS6) in a KRS-dependent manner, resulting in the M2 polarization of macrophages and subsequent secretion of soluble factors such as fibroblast growth factor 2 (FGF2), growth-regulated oncogene-α (GROα) and macrophage colony-stimulating factor (M-CSF). 109 These factors activated cancer-associated fibroblasts (CAFs) to reshape the tumour microenvironment and thus promote cancer cell dissemination. Furthermore, certain aaRSs were abnormally expressed in autoimmune diseases such as multiple sclerosis, RA and immune thrombocytopenia, suggesting that aaRSs might be associated with the immunomodulatory defects in these diseases.…”

Response gene to complement 32 expression in macrophages augments paracrine stimulation-mediated colon cancer progression

“…Some clinical studies imply an important functional contribution of TAMs to poor prognosis or recurrence of colon cancer 9,10 . It is commonly accepted that TAMs are a distinct M2-polarized population promoting tumor progression, including the promotion of tumor cell proliferation, migration and angiogenesis 11,12 . Thus, TAMs could be potential targets of therapeutic intervention.…”