Model systems and unique biological features of high and low-grade colorectal cancer (CRC) revealed by xenografting 84 human CRC cell lines

Ian Y Luk ^1,2, Jennifer K Mooi ^1,3, Dmitri Mouradov ^4,5

¹Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
²La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia.
³Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
⁴Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
⁵Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.
⁶Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
⁷Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
⁸Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
⁹Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
¹⁰Biomedical Research Institute of Lleida, IRBLleida, Lleida, Spain.
¹¹Memorial Sloan-Kettering, New York, NY, USA.
¹²Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.
¹³Institute of Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
¹⁴Department of Pathology, Austin Health, Melbourne, Victoria, Australia.
¹⁵Centre for Cancer Research, Hudson Institute for Medical Research, Monash University, Melbourne, Victoria, Australia.
¹⁶Walter and Eliza Hall Institute, Melbourne, Victoria, Australia. sieber.o@wehi.edu.au.
¹⁷Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia. sieber.o@wehi.edu.au.
¹⁸Department of Surgery, University of Melbourne, Parkville, Victoria, Australia. sieber.o@wehi.edu.au.
¹⁹Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. sieber.o@wehi.edu.au.
²⁰Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. john.mariadason@onjcri.org.au.
²¹La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia. john.mariadason@onjcri.org.au.
²²Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. john.mariadason@onjcri.org.au.

⁰Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.

Communications Biology +

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June 5, 2025

View abstract on PubMed

Summary

High-grade colorectal cancers (CRCs) show suppressed differentiation and stem cell markers, alongside increased proliferation and metastasis. These findings in cell line models accurately reflect patient tumors, offering new avenues for CRC treatment strategies.

Area Of Science

Oncology
Molecular Biology
Cancer Research

Background

Colorectal cancers (CRCs) exhibit varying differentiation grades impacting patient outcomes.
The molecular drivers of CRC differentiation status remain incompletely understood.

Purpose Of The Study

To investigate the molecular features and drivers of low-grade (LG) versus high-grade (HG) colorectal cancers.
To establish and validate cell line-derived xenograft models for studying CRC differentiation.

Main Methods

Xenografting of 84 human CRC cell lines in mice to create LG and HG models.
Transcriptional profiling to analyze gene expression differences between LG and HG tumors.
Analysis of promoter methylation and stem cell marker expression.

Main Results

HG tumors showed downregulation of differentiation factors and colonic lineage markers.
Epigenetic silencing via promoter methylation was observed in HG tumors.
HG tumors exhibited increased proliferation, migration, and metastatic capacity, with altered stem cell marker expression.

Conclusions

CRC cell lines accurately model tumor differentiation grade, as validated in patient-derived organoids and primary CRCs.
Identified molecular properties of HG CRCs may guide the development of grade-specific therapeutic strategies.

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