Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment

Xu Han; Michelle Burrows; Laura C Kim; Jimmy P Xu; Will Vostrejs; Tran Ngoc Van Le; Carson Poltorack; Yanqing Jiang; Edna Cukierman; Ben Z Stanger; Kim A Reiss; Sydney M Shaffer; Clementina Mesaros; Brian Keith; M Celeste Simon

doi:10.1016/j.celrep.2024.114972

Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment

Cell Rep. 2024 Nov 12;43(11):114972. doi: 10.1016/j.celrep.2024.114972. Online ahead of print.

Authors

Affiliations

¹ Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴ Cancer Signaling & Microenvironment Program, Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, PA 19111, USA.
⁵ Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Division of Hematology-Oncology, Penn Medicine Abramson Cancer Center, Philadelphia, PA 19104, USA.
⁷ Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: celeste2@pennmedicine.upenn.edu.

PMID: 39535921
DOI: 10.1016/j.celrep.2024.114972

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with abundant cancer-associated fibroblasts (CAFs) creating hallmark desmoplasia that limits oxygen and nutrient delivery. This study explores the importance of lipid homeostasis under stress. Exogenous unsaturated lipids, rather than de novo synthesis, sustain PDAC cell viability by relieving endoplasmic reticulum (ER) stress under nutrient scarcity. Furthermore, CAFs are less hypoxic than adjacent malignant cells in vivo, nominating them as a potential source of unsaturated lipids. CAF-conditioned medium promotes PDAC cell survival upon nutrient and oxygen deprivation, an effect reversed by delipidation. Lysophosphatidylcholines (LPCs) are particularly enriched in CAF-conditioned medium and preferentially taken up by PDAC cells, where they are converted to phosphatidylcholine (PC) to sustain membrane integrity. Blocking LPC-to-PC conversion inhibits PDAC cell survival and increases ER stress. These findings show a critical lipid "cross-feeding" mechanism that promotes PDAC cell survival, offering a potential metabolic target for treatment.

Keywords: CP: Cancer; CP: Metabolism; fibroblasts; hypoxia; lipids; pancreatic cancer; tumor microenvironment; unsaturated fatty acids.