Spatial membrane lipid remodelling encodes epithelial lineage and state in human colon cancer.

IF 11.2 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2026-10-01 Epub Date: 2026-09-10 DOI:10.1016/j.ebiom.2026.106473

Ramon M Rodriguez, Karim Pérez-Romero, Albert Maimó-Barceló, Teresa Ximelis, Cristina Huergo-Baños, Marcos A Martínez, Juan José Segura-Sampedro, Rafael Morales-Soriano, Cristina Pineño-Flores, Álvaro García-Granero, Sebastián Jerí, Ana M Aransay, José A Fernández, Gwendolyn Barceló-Coblijn

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引用次数: 0

Abstract

Background: Cancer progression is driven by spatially organised intratumoural heterogeneity, yet the molecular basis of this organisation remains incompletely understood. While spatial transcriptomics has advanced rapidly, the spatial architecture and functional relevance of tumour lipid metabolism remain poorly characterised. We aimed to resolve whether membrane phospholipid remodelling is spatially organised across epithelial cell states in human colon cancer.

Methods: We developed an integrative spatial multi-omic strategy linking mass spectrometry imaging to transcriptome-defined cellular states on consecutive tissue sections from primary and intraperitoneal metastatic human colon cancer specimens. Epithelial lipid phenotypes were characterised, validated in an independent cohort, and linked to transcriptional programmes.

Findings: We identified four spatially organised epithelial lipid phenotypes defined by membrane phospholipid composition. These phenotypes aligned with transcriptional programmes reflecting epithelial lineage and differentiation state, and were organised along a differentiation axis marked by coordinated remodelling of arachidonic acid-, oleic acid-, and linoleic acid-containing phospholipids. Secretory-associated states, enriched in metastatic lesions, showed increased DHA-containing phospholipids and activation of peroxisomal pathways. Lipid phenotype assignments were reproducible across an independent cohort.

Interpretation: Membrane phospholipid composition encodes biologically meaningful epithelial cell states within human tumours, establishing lipid remodelling as a structured and spatially organised dimension of tumour heterogeneity.

Funding: This study was supported by the ISCIII (PI19/00002, PI24/00313), the Health Research Institute of the Balearic Islands (IMP22/04), the Government of the Balearic Islands (AP_2021_001), the Basque Government (IT1491-22), the European Regional Development Fund, and the Scientific Foundation, Spanish Association Against Cancer (INVES222995RODR).

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空间膜脂重构编码人结肠癌上皮细胞谱系和状态。

背景：肿瘤的进展是由肿瘤内的空间组织异质性驱动的，然而这种组织的分子基础仍然不完全清楚。虽然空间转录组学发展迅速，但肿瘤脂质代谢的空间结构和功能相关性仍然很差。我们的目的是解决膜磷脂重塑是否在人类结肠癌上皮细胞状态的空间组织。方法：我们开发了一种综合空间多组学策略，将质谱成像与转录组定义的细胞状态联系起来，这些细胞状态来自原发性和腹腔内转移性人类结肠癌标本的连续组织切片。上皮脂质表型被表征，在一个独立的队列中验证，并与转录程序相关联。研究结果：我们确定了四种由膜磷脂组成定义的空间组织上皮脂质表型。这些表型与反映上皮谱系和分化状态的转录程序一致，并沿着以花生四烯酸、油酸和亚油酸含磷脂的协调重建为标志的分化轴组织。分泌相关状态，在转移性病变中丰富，显示含有dha的磷脂增加和过氧化物酶体途径的激活。脂质表型分配在独立队列中是可重复的。解释：膜磷脂组成编码人类肿瘤中具有生物学意义的上皮细胞状态，将脂质重塑建立为肿瘤异质性的结构和空间组织维度。资助：本研究得到了ISCIII （PI19/00002, PI24/00313）、巴利阿里群岛卫生研究所（IMP22/04）、巴利阿里群岛政府（AP_2021_001）、巴斯克政府（IT1491-22）、欧洲区域发展基金和科学基金会、西班牙抗癌协会（INVES222995RODR）的支持。

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

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.