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

Abstract

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.

• Authors: Matteo Rossi Sebastiano, Chiara Pozzato, Maria Saliakoura, Zhang Yang, Ren-Wang Peng, Mirco Galiè, Kevin Oberson, Hans-Uwe Simon, Evanthia Karamitopoulou, Georgia Konstantinidou
• Journal: Science advances (Sci Adv) Vol. 6 Issue 44 (10 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 33127675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

Chemical References

• Plasminogen Activator Inhibitor 1
• Serpin E2
• Serpine2 protein, mouse
• Acsl3 protein, mouse
• Coenzyme A Ligases

Topics

• Animals
• Carcinoma, Pancreatic Ductal (metabolism)
• Cell Line, Tumor
• Coenzyme A Ligases (genetics)
• Fibrosis
• Mice
• Pancreatic Neoplasms (pathology)
• Plasminogen Activator Inhibitor 1 (genetics)
• Serpin E2