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Peer-reviewedCC BY 4.0Oncogene

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

  • Hiroyuki Arai1,2
  • Andrew Elliott3
  • Yan Yang4
  • Alex Farrell3
  • Joshua Millstein4
  • Fang-Shu Ou5
  • Federico Innocenti6
  • Jingyuan Wang1
  • Francesca Battaglin1
  • Priya Jayachandran1
  • Sandra Algaze1
  • Shivani Soni1
13 more authors
  • Wu Zhang1
  • Richard M. Goldberg7
  • Michael J. Hall8
  • Aaron James Scott9
  • Jimmy J. Hwang10
  • Emil Lou11
  • Benjamin A. Weinberg12
  • John Marshall12
  • Sanjay Goel13
  • Joanne Xiu3
  • W. Michael Korn3
  • Alan P. Venook14
  • Heinz-Josef Lenz1
14 affiliations
  1. 1Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA USA
  2. 2Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
  3. 3Clinical & Translational Research, Medical Affairs, Caris Life Sciences, Phoenix, AZ USA
  4. 4Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA USA
  5. 5Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN USA
  6. 6UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
  7. 7West Virginia University Cancer Institute, Morgantown, WV USA
  8. 8Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA USA
  9. 9Division of hematology/oncology, University of Arizona Cancer Center, Tucson, AZ USA
  10. 10Department of Solid Tumor Oncology, GI Medical Oncology, Levine Cancer Institute, Charlotte, NC USA
  11. 11Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN USA
  12. 12Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC USA
  13. 13Department of Medical Oncology, Rutgers Cancer Institute, New Brunswick, NJ USA
  14. 14University of California, San Francisco, San Francisco, CA USA
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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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Cite

BibTeXRIS
BibTeX
@article{arai2026activation,
  title = {{Activation of the endocytosis pathway stratifies subtypes and therapeutic sensitivity in colorectal cancer}},
  author = {Hiroyuki Arai and Andrew Elliott and Yan Yang and Alex Farrell and Joshua Millstein and Fang-Shu Ou and Federico Innocenti and Jingyuan Wang and Francesca Battaglin and Priya Jayachandran and Sandra Algaze and Shivani Soni and Wu Zhang and Richard M. Goldberg and Michael J. Hall and Aaron James Scott and Jimmy J. Hwang and Emil Lou and Benjamin A. Weinberg and John Marshall and Sanjay Goel and Joanne Xiu and W. Michael Korn and Alan P. Venook and Heinz-Josef Lenz},
  journal = {Oncogene},
  year = {2026},
  month = oct,
  doi = {10.1038/s41388-026-04019-w},
  url = {https://doi.org/10.1038/s41388-026-04019-w},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Activation of the endocytosis pathway stratifies subtypes and therapeutic sensitivity in colorectal cancer
AU  - Hiroyuki Arai
AU  - Andrew Elliott
AU  - Yan Yang
AU  - Alex Farrell
AU  - Joshua Millstein
AU  - Fang-Shu Ou
AU  - Federico Innocenti
AU  - Jingyuan Wang
AU  - Francesca Battaglin
AU  - Priya Jayachandran
AU  - Sandra Algaze
AU  - Shivani Soni
AU  - Wu Zhang
AU  - Richard M. Goldberg
AU  - Michael J. Hall
AU  - Aaron James Scott
AU  - Jimmy J. Hwang
AU  - Emil Lou
AU  - Benjamin A. Weinberg
AU  - John Marshall
AU  - Sanjay Goel
AU  - Joanne Xiu
AU  - W. Michael Korn
AU  - Alan P. Venook
AU  - Heinz-Josef Lenz
PY  - 2026
DA  - 2026/10/19
JO  - Oncogene
DO  - 10.1038/s41388-026-04019-w
UR  - https://doi.org/10.1038/s41388-026-04019-w
AB  - 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.
SN  - 0950-9232
SN  - 1476-5594
ER  -