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

Autor:	Han X; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Burrows M; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Kim LC; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Xu JP; Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA., Vostrejs W; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Van Le TN; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Poltorack C; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Jiang Y; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Cukierman E; Cancer Signaling & Microenvironment Program, Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, PA 19111, USA., Stanger BZ; 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., Reiss KA; Division of Hematology-Oncology, Penn Medicine Abramson Cancer Center, Philadelphia, PA 19104, USA., Shaffer SM; 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., Mesaros C; Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA., Keith B; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Simon MC; 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.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Nov 12; Vol. 43 (11), pp. 114972. Date of Electronic Publication: 2024 Nov 12.
DOI:	10.1016/j.celrep.2024.114972
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu