Activation of the endocytosis pathway stratifies subtypes and therapeutic sensitivity in colorectal cancer
Abstract
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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Authors: Hiroyuki Arai, Andrew Elliott, Yan Yang, Alex Patrick Farrell, Joshua Millstein, Fang‐Shu Ou, Federico Innocenti, Jingyuan Wang, Francesca Battaglin, Priya Jayachandran, Sandra D. Algaze, Shivani Soni, Wu Zhang, Richard M. Goldberg, Michael J. Hall, Aaron James Scott, Jimmy J. Hwang, Emil Lou, Benjamin Adam Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, Wolfgang Michael Korn, Alan Paul Venook, Heinz‐Josef Lenz
Institutions: Georgetown University, University of North Carolina at Chapel Hill, University of California, San Francisco, University of Southern California, University of Minnesota, Fox Chase Cancer Center, West Virginia University, Mayo Clinic, St. Marianna University School of Medicine, USC Norris Comprehensive Cancer Center, Levine Cancer Institute, Rutgers Cancer Institute, Caris Life Sciences (United States), Georgetown Lombardi Comprehensive Cancer Center, University of Arizona Cancer Center