{
  "id": 3761709,
  "title": "Prognostic stratification by LGR5 expression identifies surface-accessible, structurally ligandable and condensate-forming targets in colorectal cancer",
  "url": "https://urgent.news/2026/08/27/prognostic-stratification-by-lgr5-expression-identifies-surface",
  "topic": "health",
  "section": "Health & Medicine",
  "published": "2026-08-27T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747295v1?rss=1"
  },
  "original_language": "en",
  "account": "LGR5, a marker of colorectal cancer stem cells, is frequently linked to unfavorable patient outcomes. However, its expression on regular intestinal stem cells has limited direct therapeutic targeting. Moreover, the molecular makeup of LGR5-high tumors remains largely unclear.\n\nTo reassess LGR5-high colorectal tumors, researchers used a novel approach to stratify 396 tumors from The Cancer Genome Atlas. This involved comparing the transcriptional, genetic mutation, and copy number profiles between LGR5-high and LGR5-low groups. They employed non-parametric testing, including combined significance and effect-size thresholds, to ensure rigorous analysis.\n\nThrough genome-wide CRISPR knockout data, the team evaluated genetic dependency. Each signature gene was then assessed for pharmacological tractability, evaluating three key factors: surface accessibility, cavity ligandability, and condensate propensity. Surface accessibility was determined using surfaceome annotation and membrane topology, while cavity ligandability was assessed via pocket detection on predicted protein structures using three independent algorithms. Lastly, condensate tendency was gauged through saturation concentration prediction and coarse-grained molecular dynamics simulation.\n\nThe results unveiled a coordinated program in LGR5-high tumors, involving Wnt signaling, stemness, and matrix remodeling. These tumors often arise from APC mutations in conjunction with IGF2 amplification. Despite the absence of genetic dependency, the study identified three candidate targets through modality triaging rather than focusing on essentiality. These targets were ENPP3, a single-pass ectoenzyme with an accessible ectodomain and a prior clinical antibody-drug conjugate precedent; PLCB4, which features a well-defined catalytic pocket and additional predicted ligandable sites; and NKD1, an enzyme that lacks accessibility to either surface or pocket-based approaches but undergoes RNA-stabilized homotypic phase separation.\n\nInterestingly, simulations indicated that NKD1 forms DVL2-containing condensates and diminishes DVL2-Wnt interactions. This suggests a biophysical mechanism for NKD1's negative feedback role, offering a novel therapeutic avenue. In conclusion, LGR5 expression identifies a subset of colorectal cancer tumors that, despite the lack of genetic dependency, exhibit pharmacological tractability. By triaging targets based on modality rather than essentiality, researchers can transform descriptive tumor signatures into testable therapeutic hypotheses, including novel condensate-directed modulation strategies for NKD1 targets.",
  "summary": "Background: LGR5 marks colorectal cancer stem cells and is associated with poor outcome, but its expression on normal intestinal stem cells has constrained direct therapeutic targeting, and the molecular landscape of LGR5-high tumors remains incompletely defined. A transcriptional signature is not itself a set of drug targets: its constituent genes differ in whether and how they can be engaged…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}