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

Heinz Lenz1, Hiroyuki Arai2, Andrew Elliott3

  • 1university of southern California.

Research Square
|July 10, 2026
PubMed

Insights

Endocytosis pathways vary in colorectal cancer (CRC) subtypes and link to oncogenic signaling. Low AP2M1 expression in CRC may predict better survival with anti-EGFR therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Endocytosis regulates receptor trafficking and signaling, crucial for cell function.
  • The specific role of endocytosis in colorectal cancer (CRC) progression and treatment response is not well understood.

Purpose of the Study:

  • To investigate the role of endocytosis pathways, including clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway, in CRC.
  • To correlate endocytosis gene expression with CRC molecular subtypes (CMS) and oncogenic signaling pathways.
  • To assess the association of endocytosis-related genes with clinical outcomes in metastatic CRC patients.

Main Methods:

  • Analysis of transcriptomic data from 15,025 CRC tumors.
  • Comparison of pathway-level signatures across consensus molecular subtypes (CMS).
  • Evaluation of individual endocytosis gene associations with clinical outcomes in a randomized trial cohort (CALGB/SWOG 80405).

Main Results:

  • CME and ESCRT pathway expression differed across CMS, notably higher in CMS4 and lower in CMS3.
  • Endocytosis signatures correlated with multiple oncogenic signaling pathways (MAPK, TGF-β, WNT, PI3K, NOTCH, angiogenesis).
  • Low expression of AP2M1 (a CME component) was linked to improved overall and progression-free survival in patients receiving anti-EGFR therapy, but not anti-VEGF therapy.

Conclusions:

  • Endocytic trafficking is associated with oncogenic signaling and may influence therapeutic benefit in metastatic CRC.
  • Endocytosis pathways reveal biologically relevant heterogeneity in CRC.
  • Endocytosis gene expression may aid in therapeutic stratification for CRC patients.

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