Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis

被引：8

作者：

Hendrikson, Josephine ^{[1
,2
,3
]}

Liu, Ying ^{[1
,2
,3
]}

Ng, Wai Har ^{[1
,2
,3
]}

Lee, Jing Yi ^{[4
]}

Lim, Abner Herbert ^{[4
]}

Loh, Jui Wan ^{[4
]}

Ng, Cedric C. Y. ^{[5
]}

Ong, Whee Sze ^{[6
]}

Tan, Joey Wee-Shan ^{[1
,2
,3
]}

Tan, Qiu Xuan ^{[1
,2
,3
]}

Ng, Gillian ^{[1
,2
,3
]}

Shannon, Nicholas B. ^{[1
,2
,3
]}

Lim, Weng Khong ^{[7
,8
]}

Lim, Tony K. H. ^{[9
,10
]}

Chua, Clarinda ^{[11
]}

Wong, Jolene Si Min ^{[1
,2
,12
,13
]}

Tan, Grace Hwei Ching ^{[1
,2
]}

So, Jimmy Bok Yan ^{[14
,15
]}

Yeoh, Khay Guan ^{[16
,17
]}

Teh, Bin Tean ^{[5
,18
]}

Chia, Claramae Shulyn ^{[1
,2
,12
,13
]}

Soo, Khee Chee ^{[1
,2
]}

Kon, Oi Lian ^{[3
]}

Tan, Iain Beehuat ^{[8
,11
,19
]}

Chan, Jason Yongsheng ^{[4
,11
]}

Teo, Melissa Ching Ching ^{[1
,2
]}

Ong, Chin-Ann J. ^{[1
,2
,3
,12
,13
,18
]}

机构：

[1] Natl Canc Ctr Singapore, Div Surg & Surg Oncol, Dept Sarcoma Peritoneal & Rare Tumours SPRinT, 11 Hosp Cresent, Singapore 169610, Singapore

[2] Singapore Gen Hosp, Div Surg & Surg Oncol, Dept Sarcoma Peritoneal & Rare Tumours SPRinT, Singapore 169608, Singapore

[3] Natl Canc Ctr Singapore, Div Med Sci, Lab Appl Human Genet, Singapore 169610, Singapore

[4] Natl Canc Ctr Singapore, Canc Discovery Hub, Singapore 169610, Singapore

[5] Natl Canc Ctr Singapore, Div Med Sci, Lab Canc Epigenome, Singapore 169610, Singapore

[6] Natl Canc Ctr Singapore, Div Clin Trials & Epidemiol Sci, Singapore 169610, Singapore

[7] Natl Heart Ctr Singapore, SingHlth Duke NUS Inst Precis Med, Singapore 169609, Singapore

[8] Duke NUS Med Sch, Canc & Stem Biol Signature Res Program, Singapore 169857, Singapore

[9] Singapore Gen Hosp, Dept Anat Pathol, Singapore, Singapore

[10] SingHlth Duke NUS Acad Med Ctr, Pathol Acad Clin Program, Singapore 168753, Singapore

[11] Natl Canc Ctr Singapore, Div Med Oncol, Singapore 169610, Singapore

[12] Duke NUS Med Sch, SingHlth Duke NUS Oncol Acad Clin Program, Singapore 169857, Singapore

[13] Duke NUS Med Sch, SingHlth Duke NUS Surg Acad Clin Program, Singapore 169857, Singapore

[14] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 119077, Singapore

[15] Natl Univ Hlth Syst, Natl Univ Canc Inst, Div Surg Oncol, Singapore 119074, Singapore

[16] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119077, Singapore

[17] Natl Univ Singapore Hosp, Dept Gastroenterol & Hepatol, Singapore 119074, Singapore

[18] A STAR Res Ent, Inst Mol & Cell Biol, Singapore 138673, Singapore

[19] A STAR Res Ent, Genome Inst Singapore, Lab Appl Canc Genom, Singapore 138672, Singapore

来源：

CELL REPORTS MEDICINE | 2022年 / 3卷 / 02期

基金：

英国医学研究理事会;

关键词：

PLASMINOGEN-ACTIVATOR INHIBITOR-1; ENDOTHELIAL GROWTH-FACTOR; OVARIAN-CANCER; COMBINATION CHEMOTHERAPY; MALIGNANT ASCITES; METASTASIS; PROMOTES; EXPRESSION; ALIGNMENT; BLOCKADE;

D O I：

10.1016/j.xcrm.2022.100526

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space.

引用

页数：24

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