Activation of the endocytosis pathway stratifies subtypes and therapeutic sensitivity in colorectal cancer.

IF 9.1 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2026-10-19 DOI:10.1038/s41388-026-04019-w

Hiroyuki Arai, Andrew Elliott, Yan Yang, Alex Farrell, Joshua Millstein, Fang-Shu Ou, Federico Innocenti, Jingyuan Wang, Francesca Battaglin, Priya Jayachandran, Sandra Algaze, Shivani Soni, Wu Zhang, Richard M Goldberg, Michael J Hall, Aaron James Scott, Jimmy J Hwang, Emil Lou, Benjamin A Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, W Michael Korn, Alan P Venook, Heinz-Josef Lenz

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引用次数: 0

Abstract

Endocytosis regulates receptor trafficking and signaling, yet its role in colorectal cancer (CRC) remains unclear. We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-β, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB/SWOG 80405 trial, low expression of AP2M1-a core adaptor in the CME complex-was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.

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内吞作用通路的激活使结直肠癌的亚型和治疗敏感性分层。

内吞作用调节受体运输和信号传导，但其在结直肠癌（CRC）中的作用尚不清楚。我们分析了15025例结直肠癌肿瘤的转录组学数据，以评估网格蛋白介导的内噬作用（CME）和运输所需的内体分选复合物（ESCRT）途径中的基因表达。途径水平的特征在共识分子亚型（CMS）之间进行比较，并检查与致癌信号程序的关系，同时在独立的随机试验队列中评估个体内吞相关基因与临床结果的关联。CME和ESCRT通路的表达因CMS而异，CMS4表达量最高，CMS3表达量最低。内吞作用特征与多种致癌信号通路相关，包括MAPK、TGF-β、WNT、PI3K、NOTCH和血管生成，表明内吞活性与肿瘤生物学之间存在广泛联系。在随机III期CALGB/SWOG 80405试验中，在接受抗egfr药物治疗的患者中，ap2m1 （CME复合物中的核心接头）的低表达与更长的总生存期和无进展生存期显著相关，但与接受抗vegf药物治疗的患者无关。这些发现表明，在转移性结直肠癌患者中，内吞运输可能与致癌信号和不同的治疗效果有关。胞吞作用途径反映了结直肠癌的生物学相关异质性，可能有助于指导治疗分层。

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

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.