Necroptosis enhances ‘don’t eat me’ signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis - Details

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Pancreatic　ductal　adenocarcinoma　(PDAC)　is　a　devastating　cancer　with　dismal　prognosis　due　to　distant　metastasis,　even　in　the　early　stage.　Using　RNA　sequencing　and　multiplex　immunofluorescence,　here　we　find　elevated　expression　of　mixed　lineage　kinase　domain-like　pseudo-kinase　(MLKL)　and　enhanced　necroptosis　pathway　in　PDAC　from　early　liver　metastasis　T-stage　(T1M1)　patients　comparing　with　non-metastatic　(T1M0)　patients.　Mechanistically,　MLKL-driven　necroptosis　recruits　macrophages,　enhances　the　tumor　CD47　‘don’t　eat　me’　signal,　and　induces　macrophage　extracellular　traps　(MET)　formation　for　CXCL8　activation.　CXCL8　further　initiates　epithelial–mesenchymal　transition　(EMT)　and　upregulates　ICAM-1　expression　to　promote　endothelial　adhesion.　METs　also　degrades　extracellular　matrix,　that　eventually　supports　PDAC　liver　metastasis.　Meanwhile,　targeting　necroptosis　and　CD47　reduces　liver　metastasis　in　vivo.　Our　study　thus　reveals　that　necroptosis　facilitates　PDAC　metastasis　by　evading　immune　surveillance,　and　also　suggest　that　CD47　blockade,　combined　with　MLKL　inhibitor　GW806742X,　may　be　a　promising　neoadjuvant　immunotherapy　for　overcoming　the　T1M1　dilemma　and　reviving　the　opportunity　for　radical　surgery.　©　The　Author(s)　2024.

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[ 1 ] [Liao C.-Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 2 ] [Liao C.-Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 3 ] [Liao C.-Y.]Fuzhou University, Fuzhou, 350001, China
[ 4 ] [Li G.]Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
[ 5 ] [Kang F.-P.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 6 ] [Lin C.-F.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 7 ] [Lin C.-F.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 8 ] [Lin C.-F.]Fuzhou University, Fuzhou, 350001, China
[ 9 ] [Xie C.-K.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 10 ] [Xie C.-K.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 11 ] [Wu Y.-D.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 12 ] [Wu Y.-D.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 13 ] [Hu J.-F.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 14 ] [Hu J.-F.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 15 ] [Lin H.-Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 16 ] [Lin H.-Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 17 ] [Zhu S.-C.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 18 ] [Zhu S.-C.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 19 ] [Huang X.-X.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 20 ] [Huang X.-X.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 21 ] [Huang X.-X.]Fuzhou University, Fuzhou, 350001, China
[ 22 ] [Lai J.-L.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 23 ] [Lai J.-L.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 24 ] [Lai J.-L.]Fuzhou University, Fuzhou, 350001, China
[ 25 ] [Chen L.-Q.]Fuzhou University, Fuzhou, 350001, China
[ 26 ] [Huang Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 27 ] [Huang Y.]Fuzhou University, Fuzhou, 350001, China
[ 28 ] [Li Q.-W.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 29 ] [Li Q.-W.]Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China
[ 30 ] [Li Q.-W.]Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China
[ 31 ] [Huang L.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 32 ] [Huang L.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 33 ] [Huang L.]Fuzhou University, Fuzhou, 350001, China
[ 34 ] [Wang Z.-W.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 35 ] [Wang Z.-W.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 36 ] [Wang Z.-W.]Fuzhou University, Fuzhou, 350001, China
[ 37 ] [Tian Y.-F.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 38 ] [Tian Y.-F.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 39 ] [Tian Y.-F.]Fuzhou University, Fuzhou, 350001, China
[ 40 ] [Chen S.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
[ 41 ] [Chen S.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
[ 42 ] [Chen S.]Fuzhou University, Fuzhou, 350001, China
[ 43 ] [Chen S.]Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China
[ 44 ] [Chen S.]Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China

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Nature Communications

ISSN： 2041-1723

Year： 2024

Issue： 1

Volume： 15

1 4 . 7 0 0

JCR@2023

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