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

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-11-12 DOI:10.1016/j.celrep.2024.114972

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

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引用次数: 0

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.

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癌症相关成纤维细胞在肿瘤微环境中维持着关键的胰腺癌细胞脂质平衡。

胰腺导管腺癌（PDAC）是一种侵袭性恶性肿瘤，其大量的癌相关成纤维细胞（CAFs）会造成标志性的脱黏，从而限制氧气和营养物质的输送。本研究探讨了压力下脂质平衡的重要性。外源性不饱和脂质，而不是从头合成，可在营养物质匮乏的情况下缓解内质网（ER）压力，从而维持 PDAC 细胞的活力。此外，与邻近的恶性细胞相比，CAFs 在体内的缺氧程度较低，因此被认为是不饱和脂质的潜在来源。CAF调节培养基能在营养和氧气匮乏时促进PDAC细胞存活，而脱脂则能逆转这种效应。溶血磷脂酰胆碱（LPCs）在CAF调节培养基中特别富集，并优先被PDAC细胞吸收，在PDAC细胞中转化为磷脂酰胆碱（PC），以维持膜的完整性。阻止 LPC 转化为 PC 会抑制 PDAC 细胞的存活并增加 ER 应激。这些研究结果表明，一种关键的脂质 "交叉喂养 "机制可促进 PDAC 细胞的存活，从而为治疗提供了一个潜在的代谢靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.