比利时VIB癌症生物学中心Sarah-Maria Fendt课题组揭示了脂肪变性影响结直肠癌肝转移异质性的预后。2026年7月1日，国际知名学术期刊《自然》发表了这一成果。

本研究表明，未接受治疗的伴有肝脂肪变性的结直肠癌患者与无脂肪变性的患者相比，替代转移的发生率增加。在机制上，课题组人员发现脂肪变性促进的脂肪酸氧化通过乙酰化增加MYC的稳定性，从而增加替代转移瘤的形成。反过来，MYC激活脯氨酸合成，促进胶原蛋白的产生，促进替代转移瘤的生长。靶向MYC、P5CS或COL1A1可抑制患者源性类器官、母细胞或患者源性异种移植模型中替代转移瘤的发生和生长。结直肠癌患者肝转移的空间代谢物和蛋白质分析进一步支持了这一机制。总之，小组提供了对未接受治疗的CRC患者出现预后不良的肝转移的机制理解，确定了治疗干预的潜在靶点。

据介绍，结直肠癌（CRC）患者经常发生肝转移。这些患者的预后因其肝转移的组织病理学异质性而存在偏差。“替代性”转移患者的5年总生存率低于44.2%，而“囊化”（以前称为结缔组织增生）转移患者的5年总生存率为73.4%。然而，目前还没有批准的针对替代肝转移的治疗方法。

附：英文原文

Title: Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC

Author: Peng-Winkler, Yiming, Liu, Xiao-Zheng, Verheul, Sanne M. L., Girondel, Charlotte, Igelmann, Sebastian, Rotter, Sara Marie, Doukas, Michail, Liu, Ming, Vandekeere, Anke, Planque, Mlanie, Fernndez-Garca, Juan, Tabaris, Sbastien, Buetas-Arcas, Marta, Martnez-Martn, Sandra, Dbbe, Florian, Demicco, Margherita, Vermeire, Ines, Theile, Janine, Ceuppens, Johannes, Haesevoets, Jonas, Tobarra-Lpez, Emma, Broekaert, Dorien, Bode, Johannes Georg, Luedde, Tom, Vermeulen, Peter, Tauriello, Daniele V. F., Perez-Lopez, Raquel, Stegen, Steve, Soucek, Laura, De Oliveira, Tiago, Conradi, Lena-Christin, Siegel, Peter M., Verhoef, Cornelis, Fendt, Sarah-Maria

Issue&Volume: 2026-07-01

Abstract: Patients with colorectal cancer (CRC) frequently develop liver metastases1,2,3. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases4,5. Patients with ‘replacement’ metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with ‘encapsulated’ (previously known as desmoplastic) metastases5; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.

DOI: 10.1038/s41586-026-10686-2

Source: https://www.nature.com/articles/s41586-026-10686-2

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html