PO.TB09.02 · 肿瘤生物学
药物压力驱动的进化上调CIDEA以重编程脂质代谢并促进结直肠癌的化疗耐药
Drug pressure driven evolution upregulates CIDEA to reprogram lipid metabolism and promote chemoresistance in colorectal cancer
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背景：化疗耐药仍是结直肠癌（CRC）长期生存的主要挑战。尽管脂质代谢重编程是持续药物压力下的一种关键适应机制，但其动态变化和核心调控因子仍不明确。明确获得性耐药的克隆进化和代谢驱动因素对于鉴定治疗靶点至关重要。
方法：建立了46个CRC患者来源类器官（PDO），并进行长期、剂量递增的FOLFOX诱导以生成耐药模型。在诱导前后进行全外显子组测序（WES）和RNA-seq，以评估基因组稳定性、克隆进化和转录重塑。多队列验证采用TCGA、ICGC-ARGO以及本机构的复发肿瘤样本。针对候选基因进行了功能实验——包括脂质代谢活性、干性表型和化疗敏感性分析——随后利用过表达和敲低PDO模型，并通过异种移植评估体内效应。
结果：耐药PDO表现出更致密、更不规则的结构，腺样形态减少。早期PDO保留了原发肿瘤约80%的突变图谱；随着诱导时间延长，药物压力驱动克隆选择和基因组漂移，晚期阶段保留约60%的突变，表明PDO在长期培养中维持了肿瘤的代表性。优势克隆的拷贝数改变与基因表达相关，提示存在基因剂量效应。多组学分析揭示耐药PDO中CIDEA显著上调，伴随脂质代谢重塑以及FASN、ACACB、FABP1、CD36表达升高，同时MAPK和PI3K-Akt通路激活。在TCGA、ICGC-ARGO及复发队列中，高CIDEA表达与晚期分期和更高复发率相关。功能上，CIDEA过表达促进脂滴积累并增强脂肪酸氧化（FAO），驱动化疗耐药，而CIDEA敲低则降低FAO、下调脂质代谢基因并恢复化疗敏感性。FAO抑制逆转了CIDEA过表达细胞中的耐药。体内异种移植证实CIDEA敲低改善了化疗敏感性，而CIDEA驱动的耐药可被FAO抑制逆转。
结论：本研究阐明了CRC获得性化疗耐药所依赖的克隆进化和脂质代谢重塑，并鉴定CIDEA为通过脂滴积累和增强FAO促进耐药的关键驱动因子，凸显了其治疗潜力。
关键词：结直肠癌；化疗耐药；患者来源类器官；克隆进化；脂质代谢重编程
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ABSTRACT
BACKGROUND: Chemoresistance remains a major challenge to long-term survival in colorectal cancer (CRC). Although lipid metabolic reprogramming is a key adaptation under sustained drug pressure, its dynamic changes and core regulators remain unclear. Defining the clonal evolution and metabolic drivers of acquired resistance is essential for identifying therapeutic targets.
METHODS: Forty-six CRC PDOs were established and subjected to long-term, dose-escalating FOLFOX induction to generate resistance models. Whole-exome sequencing (WES) and RNA-seq were performed before and after induction to assess genomic stability, clonal evolution, and transcriptional remodeling. Multi-cohort validation used TCGA, ICGC-ARGO, and recurrent tumor samples from our institution. Functional assays-including lipid metabolic activity, stemness phenotype, and chemosensitivity analyses-were performed for candidate genes, followed by overexpression and knockdown PDO models to evaluate in vivo effects using xenografts.
RESULTS: Resistant PDOs exhibited denser and more irregular structures with reduced gland-like morphology. Early-stage PDOs retained ~80% of the mutational landscape of primary tumors; with prolonged induction, drug pressure drove clonal selection and genomic drift, with ~60% of mutations retained in late stages, indicating PDOs maintain tumor representativeness during long-term culture. Copy-number alterations of dominant clones correlated with gene expression, suggesting a gene-dosage effect. Multi-omics analyses revealed marked upregulation of CIDEA in resistant PDOs, accompanied by lipid metabolic remodeling and increased expression of FASN, ACACB, FABP1, CD36, along with activation of MAPK and PI3K-Akt pathways. Across TCGA, ICGC-ARGO, and recurrent cohorts, high CIDEA expression was associated with advanced stage and higher recurrence. Functionally, CIDEA overexpression promoted lipid droplet accumulation and enhanced fatty acid oxidation (FAO), driving chemoresistance, whereas CIDEA knockdown reduced FAO, downregulated lipid metabolic genes, and restored chemosensitivity. FAO inhibition reversed resistance in CIDEA-overexpressing cells. In vivo xenografts confirmed that CIDEA knockdown improved chemosensitivity, while CIDEA-driven resistance was reversed by FAO inhibition.
CONCLUSIONS: This study delineates the clonal evolution and lipid metabolic remodeling underlying acquired chemoresistance in CRC and identifies CIDEA as a key driver that promotes resistance through lipid droplet accumulation and enhanced FAO, highlighting its therapeutic potential.
Key words: Colorectal cancer; Chemoresistance; Patient-derived organoids; Clonal evolution; Lipid metabolic reprogramming
利益披露 Disclosure
H. Wan, None.