CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

被引：11

作者：

Samain, Remi ^{[1
]}

Maiques, Oscar ^{[1
]}

Monger, Joanne ^{[1
]}

Lam, Hoyin ^{[2
,3
]}

Candido, Juliana ^{[1
,4
]}

George, Samantha ^{[1
]}

Ferrari, Nicola ^{[5
,6
]}

Kohihammer, Leonie ^{[1
]}

Lunetto, Sophia ^{[7
]}

Varela, Adrian ^{[1
]}

Orgaz, Jose L. ^{[1
,8
]}

Vilardell, Felip ^{[9
]}

Olsina, Jorge Juan ^{[10
]}

Matias-Guiu, Xavier ^{[9
,11
]}

Sarker, Debashis ^{[2
]}

Biddle, Adrian ^{[7
]}

Balkwill, Frances R. ^{[1
]}

Eyles, Jim ^{[4
]}

Wilkinson, Robert W. ^{[4
]}

Kocher, Hemant M. ^{[12
,13
]}

Calvo, Fernando ^{[5
,14
]}

Wells, Claire M. ^{[2
]}

Sanz-Moreno, Victoria ^{[1
,15
]}

机构：

[1] Queen Mary Univ London, Barts Canc Inst, Ctr Tumour Microenvironm, Charterhouse Sq, London EC1M 6BQ, England

[2] Kings Coll London, Sch Canc & Pharmaceut Sci, London SE1 1UL, England

[3] GSK, R&D Portfolio, Strategy & Business Insights, GSK House,980 Great West Rd, Brentford TW8 9GS, England

[4] AstraZeneca, Oncol R&D, Cambridge CB21 6GH, England

[5] Inst Canc Res, Tumour Microenvironm Team, 237 Fulham Rd, London SW3 6JB, England

[6] AstraZeneca, Translat Sci & Expt Med, Early Resp & Immunol, BioPharmaceut R&D, Cambridge, England

[7] Queen Mary Univ London, Blizard Inst, Ctr Cell Biol & Cutaneous Res, London E1 2AT, England

[8] UAM, Inst Invest Biomed Sols Morreale CSIC, Madrid 28029, Spain

[9] Univ Lleida, Hosp Univ Arnau Vilanova, Dept Pathol, Lleida, Spain

[10] Univ Lleida, Univ Hosp Arnau Vilanova, Dept Surg, Lleida, Spain

[11] Univ Hospita Bellvitge, IRBLLEIDA, IDIBELL, CIBERONC, Lleida, Spain

[12] Queen Mary Univ London, Barts Canc Inst, Ctr Tumour Biol, Charterhouse Sq, London EC1M 6BQ, England

[13] Royal London Hosp, Barts Hlth NHS Trust, Barts & London HPB Ctr, London, England

[14] Inst Biomed & Biotecnol Cantabria, C Albert Einstein 22,E39011, Santander, Spain

[15] Breast Canc NowToby Robins Res Ctr, Inst Canc Res, Cytoskeleton & Canc Metastasis Team, 237 Fulham Rd, London SW3 6JB, England

来源：

SCIENCE ADVANCES | 2023年 / 9卷 / 42期

关键词：

DUCTAL ADENOCARCINOMA; T-CELLS; TUMOR; ROCK; PLASTICITY; ADENOSINE; PROMOTES; GENERATION; INHIBITORS; EXPRESSION;

D O I：

10.1126/sciadv.adi0244

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK-Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA-ROCK-Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73-ROCK-Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.

引用

页数：19

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