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Background: Metastasis accounts for the majority of deaths among patients with colorectal cancer (CRC). Here, the regulatory role of tumour-associated macrophages (TAMs) in CRC metastasis was explored.

Methods: Immunohistochemical (IHC) analysis of the TAM biomarker CD163 was conducted to evaluate TAM infiltration in CRC. Transwell assays and an ectopic liver metastasis model were established to evaluate the metastatic ability of tumour cells. RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC-MS) were applied to identify the differentially expressed genes and proteins in CRC cells and in TAM-derived extracellular vesicles (EVs). Cholesterol content measurement, a membrane fluidity assay and filipin staining were performed to evaluate cholesterol efflux in CRC cells.

Results: Our results showed that TAM infiltration is positively correlated with CRC metastasis. TAMs can facilitate the migration and invasion of MC-38 and CT-26 cells via EVs. According to the RNA-seq data, TAM-EVs increase cholesterol efflux and enhance membrane fluidity in CRC cells by regulating ABCA1 expression, thus affecting the motility of CRC cells. Mechanistically, DOCK7 packaged in TAM-EVs can activate RAC1 in CRC cells and subsequently upregulate ABCA1 expression by phosphorylating AKT and FOXO1. Moreover, IHC analysis of ABCA1 in patients with liver-metastatic CRC indicated that ABCA1 expression is significantly greater in metastatic liver nodules than in primary CRC tumours.

Conclusions: Overall, our findings suggest that DOCK7 delivered via TAM-EVs could regulate cholesterol metabolism in CRC cells and CRC cell metastasis through the RAC1/AKT/FOXO1/ABCA1 axis. DOCK7 could thus be a new therapeutic target for controlling CRC metastasis.

Titel:	Tumour-associated macrophage-derived DOCK7-enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis.
Autor/in / Beteiligte Person:	Chen, W ; Zhou, M ; Guan, B ; Xie, B ; Liu, Y ; He, J ; Zhao, J ; Zhao, Q ; Yan, D
Link:	Full Text Finder (Volltext)
Zeitschrift:	Clinical and translational medicine, Jg. 14 (2024-02-01), Heft 2, S. e1591
Veröffentlichung:	2020- : [Hoboken, NJ] : Wiley ; <i>Original Publication</i>: Heidelberg : Springer-Verlag, 2024
Medientyp:	academicJournal
ISSN:	2001-1326 (electronic)
DOI:	10.1002/ctm2.1591
Schlagwort:	Humans Proto-Oncogene Proteins c-akt Tumor-Associated Macrophages Cholesterol rac1 GTP-Binding Protein genetics Guanine Nucleotide Exchange Factors GTPase-Activating Proteins ATP Binding Cassette Transporter 1 Colonic Neoplasms Extracellular Vesicles
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Clin Transl Med] 2024 Feb; Vol. 14 (2), pp. e1591. MeSH Terms: Colonic Neoplasms* ; Extracellular Vesicles* ; Humans ; Proto-Oncogene Proteins c-akt ; Tumor-Associated Macrophages ; Cholesterol ; rac1 GTP-Binding Protein / genetics ; Guanine Nucleotide Exchange Factors ; GTPase-Activating Proteins ; ATP Binding Cassette Transporter 1 References: Clin Transl Med. 2024 Feb;14(2):e1591. (PMID: 38385857) ; Exp Mol Med. 2023 Sep;55(9):1982-1995. (PMID: 37653037) ; Cell Physiol Biochem. 2018;45(1):356-365. (PMID: 29402795) ; Nat Cell Biol. 2019 Apr;21(4):498-510. (PMID: 30936474) ; JAMA. 2021 Feb 16;325(7):669-685. (PMID: 33591350) ; Neuron. 2006 Sep 21;51(6):727-39. (PMID: 16982419) ; Horm Metab Res. 2016 May;48(5):338-44. (PMID: 26743528) ; Nucleic Acids Res. 2021 Apr 6;49(6):3322-3337. (PMID: 33704464) ; Bioact Mater. 2021 Aug 28;10:281-294. (PMID: 34901546) ; Cell Death Dis. 2022 Apr 20;13(4):382. (PMID: 35443741) ; Curr Opin Struct Biol. 2021 Dec;71:249-258. (PMID: 34507037) ; Lancet. 2019 Oct 19;394(10207):1467-1480. (PMID: 31631858) ; Cancer Lett. 2022 Oct 28;547:215884. (PMID: 35988817) ; Cancer Immunol Res. 2023 Feb 3;11(2):199-216. (PMID: 36512324) ; Eur J Cell Biol. 2014 Oct;93(10-12):466-77. (PMID: 25022758) ; CA Cancer J Clin. 2022 Jan;72(1):7-33. (PMID: 35020204) ; Geroscience. 2023 Jun;45(3):1889-1898. (PMID: 36856946) ; Cancer Med. 2020 Aug;9(16):5976-5988. (PMID: 32590883) ; Horm Metab Res. 2010 Feb;42(2):102-9. (PMID: 19902402) ; CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: 33538338) ; Oncol Rep. 2019 Nov;42(5):1869-1877. (PMID: 31432185) ; Theranostics. 2021 Mar 31;11(12):5794-5812. (PMID: 33897882) ; Theranostics. 2020 May 15;10(14):6122-6135. (PMID: 32483443) ; Nat Cell Biol. 2018 Mar;20(3):332-343. (PMID: 29459780) ; J Extracell Vesicles. 2020 May 31;9(1):1769373. (PMID: 33144925) ; Cell. 2006 Jan 27;124(2):263-6. (PMID: 16439202) ; J Natl Cancer Inst. 2014 Jun 23;106(7):. (PMID: 24957074) ; Curr Protoc Cell Biol. 2006 Apr;Chapter 3:Unit 3.22. (PMID: 18228490) ; J Leukoc Biol. 2009 Nov;86(5):1065-73. (PMID: 19741157) ; Crit Rev Oncol Hematol. 2008 Apr;66(1):1-9. (PMID: 17913510) ; Int J Mol Sci. 2021 Feb 05;22(4):. (PMID: 33562440) ; Oncogene. 2018 Aug;37(35):4769-4780. (PMID: 29780167) ; J Clin Invest. 2015 Jul 1;125(7):2748-58. (PMID: 26075824) ; Cancer Cell. 2011 Apr 12;19(4):541-55. (PMID: 21481794) ; Trends Pharmacol Sci. 2023 Apr;44(4):222-236. (PMID: 36828759) ; Nat Rev Dis Primers. 2021 Apr 15;7(1):27. (PMID: 33859205) ; Adv Sci (Weinh). 2022 Jan 17;9(9):2102620. (PMID: 35356153) ; Mol Ther. 2021 Jun 2;29(6):2088-2107. (PMID: 33571679) ; Cancer Sci. 2023 Mar;114(3):822-836. (PMID: 36369902) ; Trends Immunol. 2002 Nov;23(11):549-55. (PMID: 12401408) ; Trends Cell Biol. 2007 Aug;17(8):383-93. (PMID: 17765544) ; Oncoimmunology. 2015 Apr 2;4(9):e1027472. (PMID: 26405598) ; Clin Biochem. 2003 Feb;36(1):61-5. (PMID: 12554062) ; Semin Cell Dev Biol. 2018 Jun;78:13-21. (PMID: 28803894) ; Int J Biol Sci. 2021 Apr 24;17(7):1808-1820. (PMID: 33994864) ; BMC Cancer. 2020 Nov 25;20(1):1149. (PMID: 33238958) ; Cancer Res. 2004 Nov 1;64(21):7682-5. (PMID: 15520169) ; Neoplasia. 2017 Nov;19(11):868-884. (PMID: 28938158) Grant Information: 82072636 National Natural Science Foundation of China; 81871931 National Natural Science Foundation of China; 22YF14360000 Shanghai Sailing Program Contributed Indexing: Keywords: cholesterol metabolism; colorectal cancer; extracellular vesicles; metastasis; tumour-associated macrophages Substance Nomenclature: EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) ; 97C5T2UQ7J (Cholesterol) ; 0 (RAC1 protein, human) ; EC 3.6.5.2 (rac1 GTP-Binding Protein) ; 0 (DOCK7 protein, human) ; 0 (Guanine Nucleotide Exchange Factors) ; 0 (GTPase-Activating Proteins) ; 0 (ABCA1 protein, human) ; 0 (ATP Binding Cassette Transporter 1) Entry Date(s): Date Created: 20240222 Date Completed: 20240223 Latest Revision: 20240417 Update Code: 20240418 PubMed Central ID: PMC10883245

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Tumour-associated macrophage-derived DOCK7-enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis.