ACSL3-PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression.

Rossi Sebastiano, Matteo; Pozzato, Chiara; Saliakoura, Maria; Zhang, Yang; Peng, Ren-Wang; Galiè, Mirco; Oberson, Kevin; Simon, Hans-Uwe; Karamitopoulou, Evanthia; Konstantinidou, Georgia (2020). ACSL3-PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression. Science Advances, 6(44), pp. 1-15. American Association for the Advancement of Science 10.1126/sciadv.abb9200

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked fibrosis and low immunogenicity, features that are linked to treatment resistance and poor clinical outcomes. Therefore, understanding how PDAC regulates the desmoplastic and immune stromal components is of great clinical importance. We found that acyl-CoA synthetase long-chain 3 (ACSL3) is up-regulated in PDAC and correlates with increased fibrosis. Our in vivo results show that Acsl3 knockout hinders PDAC progression, markedly reduces tumor fibrosis and tumor-infiltrating immunosuppressive cells, and increases cytotoxic T cell infiltration. This effect is, at least in part, due to decreased plasminogen activator inhibitor-1 (PAI-1) secretion from tumor cells. Accordingly, PAI-1 expression in PDAC positively correlates with markers of fibrosis and immunosuppression and predicts poor patient survival. We found that PAI-1 pharmacological inhibition strongly enhances chemo- and immunotherapeutic response against PDAC, increasing survival of mice. Thus, our results unveil ACSL3-PAI-1 signaling as a requirement for PDAC progression with druggable attributes.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Rossi Sebastiano, Matteo; Pozzato, Chiara; Saliakoura, Maria; Zhang, Yang; Peng, Ren-Wang; Oberson, Kevin; Simon, Hans-Uwe; Karamitopoulou, Evanthia and Konstantinidou, Georgia

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2375-2548

Publisher:

American Association for the Advancement of Science

Language:

English

Submitter:

Celine Joray

Date Deposited:

18 Nov 2020 11:24

Last Modified:

18 Nov 2020 11:25

Publisher DOI:

10.1126/sciadv.abb9200

PubMed ID:

33127675

BORIS DOI:

10.7892/boris.148240

URI:

https://boris.unibe.ch/id/eprint/148240

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