Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway

Abstract

Pattern-recognition receptors (PRRs) have been shown to promote tumour metastasis via sensing tumour cell-derived small extracellular vesicles (EVs). Nucleotidebinding oligomerisation domain 1 (NOD1), a cytoplasmic PRR, plays a role in colorectal cancer (CRC) by detecting bacterial products. However, the precise mechanisms underlying the effects of NOD1, following identification of CRC cell-derived EVs (CRC-EVs), to potentiate CRC liver metastasis (CRC-LM), remain poorly understood. Here, we demonstrate that CRC-EVs activate NOD1 in macrophages to initiate secretion of inflammatory cytokines and chemokines. NOD1-activated macrophages also promote CRC cell migration, while in a murine model of liver metastasis (LM), NOD1-deficient mice exhibit reduced metastasis following CRC-EV treatment. Furthermore, cell division cycle 42 (CDC42), a small Rho guanosine-5′-triphosphate (GTP)ase, is delivered by CRC-EVs into macrophages where it activates NOD1. In addition, EVs from the plasma of patients with CRC-LM mediate NOD1 activation in human peripheral blood mononuclear cells. Moreover, high NOD1 expression in tumour tissues is associated with poor prognosis of CRC-LM. Our findings suggest that CRC-EVs activate NOD1 to promote tumour metastasis, thus, NOD1 may serve as a potential target in the diagnosis and treatment of CRC-LM.

Dynamic mapping of proteome trafficking within and between living cells by TransitID

“…G. Knockdown of stress-insensitive translocated proteins (MBD1 or TOPBP1), but not stress-sensitive proteins (ERC1, POLR2D or ST13), impairs cell viability under arsenite stress. 54,55 that can activate cytosolic signaling in recipient macrophages. TOMM20 and VDAC2 are mitochondrial proteins that can traffick between cells via nanotubes 57 .…”

“…Western blot analysis of enriched material showed that the proteins CDC42 and PTEN traffick between the tumor cytosol and macrophage cytosol ( Figure 7C-E ). Both proteins have previously been detected in cancer-derived exosomes 54, 55 , but the destination compartment within macrophages was unknown. We found that treatment of cultures with the exosome biogenesis inhibitor GW4869 reduced the transfer of both proteins to macrophage cytosol ( Figure 7E ).…”

“…E. Western blot detection of specific protein markers in samples from ( D ) after tandem enrichment. CDC42 and PTEN are known exosome cargoes 54, 55 that can activate cytosolic signaling in recipient macrophages. TOMM20 and VDAC2 are mitochondrial proteins that can traffick between cells via nanotubes 57 .…”

The Biological Effect of Small Extracellular Vesicles on Colorectal Cancer Metastasis

“…CRC-sEVs activated macrophage nucleotide-binding oligomerization domain 1 (NOD1) signaling and promoted secretion of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α). NOD1-activated macrophages also promoted CRC cell metastasis [ 67 ]. Takano et al found that sEVs carrying miR-203 from CRC cells were integrated into monocytes and promoted the expression of M2 markers.…”

Exosomal microRNA signature from plasma-derived extracellular vesicles in gastric cancer

“…However, in pathological conditions such as cancer, they can promote tumor invasion and metastasis. Recently, there has been much interest in the study of exosomes because they are carriers of molecules such as DNAs, coding and non-coding RNAs, lipids, and proteins that may have immunosuppressive effects or favor tumor invasion [6]. Among the non-coding RNAs, we have miRNAs, short RNAs of 18 to 22 nucleotides, which play a significant role in regulating gene expression at the posttranscriptional level [7].…”