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Background <p>Accurate pre- and intraoperative assessment of disease extent is crucial for curative treatment of colorectal liver metastases (CRLM) and primary colorectal cancer (pCRC). Tumour-targeted nuclear imaging can enhance pre- and postoperative tumour staging, while tumour-specific fluorescence-guided surgery can improve intraoperative visualization. However, validated targets remain limited, particularly for CRLM. This study aimed to identify and validate novel molecular targets for CRLM using a data-driven approach. Additional objectives included pCRC target expression and evaluating target expression in neoadjuvant-treated patients.</p> Results <p>Using a data-driven RNA-based discovery approach (Euretos), candidate targets for colorectal liver metastases were identified. Of these, the six highest-ranking targets—CEACAM5, EPCAM, CEACAM6, MUC13, FXYD3, and CDH17—were selected for validation through immunohistochemistry (IHC). Semi-automated image analysis quantified IHC staining intensity (0-100) for tumour epithelium and background on a per-pixel basis. A patient’s staining pattern was regarded as positive if mean tumour epithelium scored positive (&gt;25), background negative (&lt;25) and tumour epithelium &gt;25 points higher than background, referred to as <i>relative positive expression</i>. The proportion of CRLM samples showing relative positive expression was 79% for CEACAM5, 45% for EPCAM, 80% for CEACAM6, 24% for MUC13, 58% for FXYD3, and 22% for CDH17. CEACAM5/CEACAM6 combined positivity reached 90% (either one positive), showing that targeting both markers enables molecular imaging in nearly the entire population. Staining intensities were similar in pCRC epithelium (<i>P</i> &gt;0.05). Neoadjuvant-treated CRLM exhibited higher expression for all targets.</p> Conclusion <p>Using a novel data-driven approach, six potential imaging targets were successfully identified and validated. CEACAM5 and CEACAM6 emerged as strong targets that, regardless of neoadjuvant therapy, covered nearly the entire CRLM population—supporting their further probe development and clinical translation.</p>

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Data-driven identification and semi-automated quantification of molecular targets for tumour-imaging of colorectal liver metastases and primary colorectal tumours

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月25日

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  • Mats I. Warmerdam,
  • Nidal Amenchar,
  • Feline Hutten,
  • A. Stijn L. P. Crobach,
  • Okker D. Bijlstra,
  • Nada Badr,
  • J. Sven D. Mieog,
  • Ronald van Vlierberghe,
  • Alexander L. Vahrmeijer,
  • Peter J. K. Kuppen

摘要

Background

Accurate pre- and intraoperative assessment of disease extent is crucial for curative treatment of colorectal liver metastases (CRLM) and primary colorectal cancer (pCRC). Tumour-targeted nuclear imaging can enhance pre- and postoperative tumour staging, while tumour-specific fluorescence-guided surgery can improve intraoperative visualization. However, validated targets remain limited, particularly for CRLM. This study aimed to identify and validate novel molecular targets for CRLM using a data-driven approach. Additional objectives included pCRC target expression and evaluating target expression in neoadjuvant-treated patients.

Results

Using a data-driven RNA-based discovery approach (Euretos), candidate targets for colorectal liver metastases were identified. Of these, the six highest-ranking targets—CEACAM5, EPCAM, CEACAM6, MUC13, FXYD3, and CDH17—were selected for validation through immunohistochemistry (IHC). Semi-automated image analysis quantified IHC staining intensity (0-100) for tumour epithelium and background on a per-pixel basis. A patient’s staining pattern was regarded as positive if mean tumour epithelium scored positive (>25), background negative (<25) and tumour epithelium >25 points higher than background, referred to as relative positive expression. The proportion of CRLM samples showing relative positive expression was 79% for CEACAM5, 45% for EPCAM, 80% for CEACAM6, 24% for MUC13, 58% for FXYD3, and 22% for CDH17. CEACAM5/CEACAM6 combined positivity reached 90% (either one positive), showing that targeting both markers enables molecular imaging in nearly the entire population. Staining intensities were similar in pCRC epithelium (P >0.05). Neoadjuvant-treated CRLM exhibited higher expression for all targets.

Conclusion

Using a novel data-driven approach, six potential imaging targets were successfully identified and validated. CEACAM5 and CEACAM6 emerged as strong targets that, regardless of neoadjuvant therapy, covered nearly the entire CRLM population—supporting their further probe development and clinical translation.