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Metastatic Colorectal Cancer Cell Derived Extracellular Vesucles Aberrantly Activate Macrophages via Transfer of Neoplastic Ribosomes，eukaryotic initiation factors and tRNA ligases

ABSTRACT: Exosomes play critical roles in colorectal cancer (CRC) in terms of oncogenesis, tumor cell survival, chemo-resistance, and metastasis. We have reported the proteome of exosomes released by human and mouse CRC cells. The proteins were predominantly focused on the translation regulation. We analyzed the exosomes of EMT CRC cell and epithelial-like CRC cell, and revealed that the upregulated proteins were predominantly enriched on the translation regulation. With a novel strategy, we traced the endpoint exosomally transported translation regulation proteins from CRC cells to macrophages and fibroblasts. Hence, we hypothesize that CRC cell derived exosomes regulate the globe translation of macrophage and fibroblasts, contributing to the formation of tumor microenvironment. We then employed our well-established model by using 3 CRC cell lines and macrophages to analyze the intracellular changes in terms of transcriptome and translatome, and characterized genome-wide translation regulation. The results showed that exosomes inhibited the translation process of fibroblasts due to the high ROS input from the tumor. We found that EMT CRC exosomes could up-regulate macrophage translation genome-wide, and promoted the transformation of macrophages to TAMs phenotype. we observed the preferential up-regulation of longer genes in macrophages treated with highly metastatic CRC exosomes, but not in those treated with Caco-2 exosomes. This study systematically researched the information flow of proteins from CRC cells to exosomes and then to target cells, and tempted to address the CRC cell exosomes educated macrophages in the systems biology view, which could lead to better understanding of translational control and its contribution to tumor microenvironment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yang Wang

PROVIDER: PXD062284 | iProX | Wed Mar 26 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Exososmes, potent intercellular communicators, are supposed to contribute to metastasis formation, which we confirmed for exosomes of the metastatic rat pancreatic adenocarcinoma line BSp73ASML that promote metastatic settlement in lymph nodes and lung of poorly metastatic BSp73ASML cells with a selective CD44v4-v7 (BSp73ASML-CD44vkd) knockdown. To define the molecular pathway(s), whereby exosomes contribute to premetastatic niche preparation, we profiled mRNA miRNA of BSp73ASMLwt and BSp73ASML-CD44vkd- exosomes and evaluated the impact on potential target cells. BSp73ASML exosomes are recovered in the draining lymph node after subcutaneous injection. In vitro, they preferentially bind and are taken-up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. BSp73ASMLwt and BSp73ASML-CD44kd exosomes contain a restricted repertoire of mRNA and miRNA, hwere the lattter differe significantly between the two lines and even more pronounced, exosomes derived thereof with a not yet explored dominance of tumor-suppressor miRNA in ASML-CD44kd cells and exosomes. Both, exosomal mRNA and miRNA are recovered in target cells and exosome-uptake is accompanied by significant changes in gene expression. We didn't observe a correlation between exosomal mRNA and changes in target cell mRNA or proteins. Instead transferred miRNA significantly affected target cell mRNA translation as demonstrated for selected, most abundant ASML exosomal miRNA besides others, miR-494 known target MAL (myelin and lymphocytes protein)/cadherin17, and miR-542-3p which targets TRAF/cadherin17. Furthermore, MMP transcription suggested to accompany cadherin17 dwon-regulation was upregulated in miR-494 or miR542-3p transfected or exosome co-cultured LnStr. Taken together, tumor exosomes target in vivo non-transformed cells in premetastatic organs. Exosome uptake induced altered target celll gene expression is strongly promoted by exosomal miRNA where we demonstrate for the first time that exosomes/exosomal miRNA from a metastasizing tumor line can modulate stroma cells from premetastatic organs. Endothelial cells lines were treated with pancreatic adenocarcinoma (AS) derived exosomes or pancreatic adenocarcinoma derived exosomes expressing tetraspanin 8. Total RNA was isolated and used to perform the Agilent gene expression microarrays. In this assay a replicate of endothelial cell lines treated with ASTspan8 were also included. Moreover, total RNA from both base line expression of endothelial cells and rat endothelial fibroblasts were also used to perfrom gene expression microarrays. RNA isolated from Rat endothelial fibroblasts treated with the exosomes derived from rat pancreatic adenocarcinoma and exosomes derived from rat pancreatic adenocarcinoma expressing tetraspanin8 were individually used to perfrom gene expression microarrays. RNA isolated from exosomes derived from rat pancreatic adenocarcinoma cell lines expressing tetraspanin were used to peform gene expresiion to see the base line expression. Another replicate were also used. RNA isolated from base line or control of rat pancreatic adenocarcinoma wild type cells and also base line RNA isolated from rat pancreatic adenocarcinoma cells lines where CD44 was knock-down.

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Metastatic Colorectal Cancer Cell Derived Extracellular Vesucles Aberrantly Activate Macrophages via Transfer of Neoplastic Ribosomes，eukaryotic initiation factors and tRNA ligases

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