A regenerative stem cell phenotype marked by ANXA1 defines aggressive colorectal cancer biology
- 1University Hospital Basel
Abstract
Background: LGR5 and ANXA1 are markers for specific intestinal stem cell states. LGR5+/ANXA1- crypt base columnar cells (CBCs) maintain homeostasis, whereas ANXA1+/LGR5- regenerative stem cells (RSCs) are present in fetal and repairing epithelium. Both states have been described in colorectal cancer (CRC), yet their clinical significance remains unclear. We aimed to determine how ANXA1 and LGR5 expression relates to molecular subtype, immune microenvironment and outcome in CRC. Methods: Dual-colour in situ hybridisation for ANXA1 and LGR5 was performed on tissue microarrays from 2163 patients in the randomised SCOT trial (ISRCTN59757862). AI-based digital pathology quantified marker-positive area by compartment and image based consensus molecular subtype (imCMS). Markers were related to clinicopathological, molecular and immune data, and to survival using Kaplan-Meier and multivariable Cox analyses. Results: ANXA1 and LGR5 showed inverse enrichment among a diverse group of parameters. ANXA1 was highest in CMS1 and LGR5 in CMS2, with CMS3 and CMS4 being intermediate. ANXA1 dominance was associated with right-sidedness, mismatch repair deficiency, BRAF-V600E mutation, high stromal content, T4 stage, low stromal FoxP3 and high epithelial CD68 density. Combining both markers improved prognostic discrimination compared with either alone (cancer-specific survival p<0.001; recurrence-free interval p=0.004), with ANXA1 dominance remaining an independent predictor of recurrence after adjustment (HR 1.43, 95% CI 1.08-1.90, p=0.014). Conclusion: Relative ANXA1 enrichment defines an aggressive, stroma-rich, macrophage-enriched CRC subgroup with poor prognosis.
Related
- MCT1 activity defines an aggressive metabolic phenotype and therapeutic target in non-small cell lung cancer
- Perineural invasion is associated with an aggressive phenotype and reduced in vitro capecitabine sensitivity in colorectal cancer
- Precision Orthobiologics for Chronic Musculoskeletal Pain: Matching Biology, Pathology, and Patient Phenotype-A Narrative Review of Current Evidence and Future Directions in Regenerative Pain Medicine.
- Spatial epigenomics reveals ancestry-associated regulatory states linked to aggressive prostate cancer biology
- SPINT2 Is Associated with Dual-Phenotype Hepatocellular Carcinoma and Aggressive Tumor Features.
BibTeX
@misc{rottewettig2026regenerative,
title = {{A regenerative stem cell phenotype marked by ANXA1 defines aggressive colorectal cancer biology}},
author = {H. S. Rotte-Wettig and E. Domingo and G. Valbuena and N. Nasreddin and A. Harkin and T. Iveson and M. P. Saunders and K. A. Oien and N. Maka and F. Pezzella and L. Campo and M. Browne and M. Glaire and J. Hay and J. Edwards and O. J. Sansom and C. Kelly and I. Tomlinson and R. Kerr and D. Kerr and TransSCOT consortium and imCMS Consortium and S. Leedham and D. N. Church and K. Braeutigam and V. H. Koelzer},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.26366700},
url = {https://www.medrxiv.org/content/10.64898/2026.10.28.26366700v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A regenerative stem cell phenotype marked by ANXA1 defines aggressive colorectal cancer biology
AU - H. S. Rotte-Wettig
AU - E. Domingo
AU - G. Valbuena
AU - N. Nasreddin
AU - A. Harkin
AU - T. Iveson
AU - M. P. Saunders
AU - K. A. Oien
AU - N. Maka
AU - F. Pezzella
AU - L. Campo
AU - M. Browne
AU - M. Glaire
AU - J. Hay
AU - J. Edwards
AU - O. J. Sansom
AU - C. Kelly
AU - I. Tomlinson
AU - R. Kerr
AU - D. Kerr
AU - TransSCOT consortium
AU - imCMS Consortium
AU - S. Leedham
AU - D. N. Church
AU - K. Braeutigam
AU - V. H. Koelzer
PY - 2026
DA - 2026/10/28
PB - medRxiv
DO - 10.64898/2026.10.28.26366700
UR - https://www.medrxiv.org/content/10.64898/2026.10.28.26366700v1
AB - Background: LGR5 and ANXA1 are markers for specific intestinal stem cell states. LGR5+/ANXA1- crypt base columnar cells (CBCs) maintain homeostasis, whereas ANXA1+/LGR5- regenerative stem cells (RSCs) are present in fetal and repairing epithelium. Both states have been described in colorectal cancer (CRC), yet their clinical significance remains unclear. We aimed to determine how ANXA1 and LGR5 expression relates to molecular subtype, immune microenvironment and outcome in CRC. Methods: Dual-colour in situ hybridisation for ANXA1 and LGR5 was performed on tissue microarrays from 2163 patients in the randomised SCOT trial (ISRCTN59757862). AI-based digital pathology quantified marker-positive area by compartment and image based consensus molecular subtype (imCMS). Markers were related to clinicopathological, molecular and immune data, and to survival using Kaplan-Meier and multivariable Cox analyses. Results: ANXA1 and LGR5 showed inverse enrichment among a diverse group of parameters. ANXA1 was highest in CMS1 and LGR5 in CMS2, with CMS3 and CMS4 being intermediate. ANXA1 dominance was associated with right-sidedness, mismatch repair deficiency, BRAF-V600E mutation, high stromal content, T4 stage, low stromal FoxP3 and high epithelial CD68 density. Combining both markers improved prognostic discrimination compared with either alone (cancer-specific survival p<0.001; recurrence-free interval p=0.004), with ANXA1 dominance remaining an independent predictor of recurrence after adjustment (HR 1.43, 95% CI 1.08-1.90, p=0.014). Conclusion: Relative ANXA1 enrichment defines an aggressive, stroma-rich, macrophage-enriched CRC subgroup with poor prognosis.
ER -