LGR5-high colorectal cancer defines a Wnt-active stem-like state with multimodal therapeutic vulnerabilities

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) marks a stem-like colorectal cancer population but is difficult to target directly because of its expression in normal intestinal stem cells. Here, we integrated transcriptomic, somatic mutation, and copy-number data from 396 colorectal tumors to define the LGR5-high molecular state and identify therapeutic vulnerabilities through modality-matched tractability analysis. LGR5-high tumors displayed a coordinated Wnt-active, stem-like transcriptional program associated with extracellular matrix remodeling, APC mutations, and IGF2 amplification, yet lacked selective genetic dependencies among the identified genes. We therefore assessed candidate targets across three complementary dimensions: surface accessibility, structural ligandability, and biomolecular condensate behavior.

ENPP3 emerged as the strongest candidate for antibody-based delivery, combining tumor-associated expression, an accessible ectodomain, internalization capacity, and clinical antibody-drug conjugate precedent. PLCB4 showed the strongest structural ligandability, with independent algorithms identifying its catalytic site and additional predicted cavities. NKD1 lacked conventional ligandable pockets but formed RNA-stabilized condensates and partitioned into DVL2-AXIN1 assemblies, reducing AXIN1 self-association and DVL2-AXIN1 contacts in molecular simulations. Together, these findings define LGR5-high colorectal cancer as a therapeutically tractable molecular state and establish a modality-matched framework for translating tumor-associated signatures into experimentally testable therapeutic hypotheses.