Phosphatidylserine Synthase PTDSS1 Shapes the Tumor Lipidome to Maintain Tumor-Promoting Inflammation.

Abstract

An altered lipidome in tumors may affect not only tumor cells themselves but also their microenvironment. In this study, a lipidomics screen reveals increased amounts of phosphatidylserine (PS), particularly ether-PS (ePS), in murine mammary tumors compared with normal tissue. PS was produced by phosphatidylserine synthase 1 (PTDSS1), and depletion of Ptdss1 from tumor cells in mice reduced ePS levels accompanied by stunted tumor growth and decreased tumor-associated macrophage (TAM) abundance. Ptdss1-deficient tumor cells exposed less PS during apoptosis, which was recognized by the PS receptor MERTK. Mammary tumors in macrophage-specific Mertk-/- mice showed similarly suppressed growth and reduced TAM infiltration. Transcriptomic profiles of TAMs from Ptdss1-knockdown tumors and Mertk-/- TAMs revealed that macrophage proliferation was reduced when the Ptdss1/Mertk pathway was targeted. Moreover, PTDSS1 expression correlated positively with TAM abundance but negatively with breast carcinoma patient survival. PTDSS1 thus may be a target to modify tumor-promoting inflammation.

SIGNIFICANCE:

This study shows that inhibiting the production of ether-phosphatidylserine by targeting phosphatidylserine synthase PTDSS1 limits tumor-associated macrophage expansion and breast tumor growth.

• Authors: Divya Sekar, Christina Dillmann, Evelyn Sirait-Fischer, Annika F Fink, Aleksandra Zivkovic, Natalie Baum, Elisabeth Strack, Stephan Klatt, Sven Zukunft, Stefan Wallner, Arnaud Descot, Catherine Olesch, Priscila da Silva, Andreas von Knethen, Tobias Schmid, Sabine Grösch, Rajkumar Savai, Nerea Ferreirós, Ingrid Fleming, Sourav Ghosh, Carla V Rothlin, Holger Stark, Hind Medyouf, Bernhard Brüne, Andreas Weigert
• Journal: Cancer research (Cancer Res) Vol. 82 Issue 8 Pg. 1617-1632 (04 15 2022) ISSN: 1538-7445 [Electronic] United States
• PMID: 35425959 (Publication Type: Journal Article)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Phosphatidylserines
• Ether
• c-Mer Tyrosine Kinase
• CDPdiacylglycerol-Serine O-Phosphatidyltransferase

Topics

• Animals
• CDPdiacylglycerol-Serine O-Phosphatidyltransferase
• Ether
• Humans
• Inflammation (metabolism)
• Lipidomics
• Mice
• Neoplasms (metabolism)
• Phosphatidylserines (metabolism)
• Tumor Microenvironment
• c-Mer Tyrosine Kinase (metabolism)