Perturbations in the ligand-receptor interactions unravel novel heterogeneous subtypes of stage II/III colorectal cancer

Abstract

Approximately 10%-15% of stage II and 25%-30% of stage III colorectal cancer (CRC) patients experience recurrence within five years after surgery, while existing taxonomies are inadequate for daily clinical application. Therefore, a more reliable classification approach with higher accuracy and prognostic potential is urgently required to stratify stage II/III CRC and identify potential patients who will benefit from postoperative adjuvant therapy. Alternatively, interactions of ligand-receptor pairs point to an emerging direction in tumor signaling with far-reaching implications for CRC, while their impact on tumor subtyping has not been elucidated. Herein, 304 normal samples, 1,386 stage II/III CRC patients, and 2,557 ligand-receptor pairs were retrospectively retrieved. Grounded on perturbations in ligand-receptor interactions, four well-characterized and robust ligand-receptor-driven subtypes (LRDS1-4) were established in the discovery cohort and validated in meta-GEO cohort comprising nine independent cohorts. Specifically, LRDS1 was characterized by an immune-cold phenotype, with cell proliferation and differentiation-related functions and higher tumor purity; LRDS2 was endowed with matrix activation-related pathways and sensitive to fluorouracil-based chemotherapy; LRDS3 was distinguished by elevated metabolic activities and frequent 13q12.2 amplification; LRDS4 was an immune-hot subtype, driven by mutations, and exhibiting dismal prognosis with MEIS2 as the prognostic feature gene. Overall, our study developed four heterogeneous LRDS and shed novel insights into the implications of intercellular communication on stage II/III CRC from a ligand-receptor interactome perspective.