Hidden metastases reveal clues to colorectal cancer recurrence
UT MD Anderson Research News July 09, 2026
- Microscopic colorectal cancer liver metastases harbor features that enable cancer cells to survive treatment and drive disease recurrence
- Researchers identified a six-gene signature in micrometastases associated with minimal residual disease, recurrence risk and chemotherapy resistance
- Findings may support future tissue-based tools to improve recurrence monitoring after treatment
Researchers at The University of Texas MD Anderson Cancer Center identified a six-gene signature in microscopic colorectal cancer (CRC) liver metastases that may help predict recurrence after treatment. The findings suggest these tiny, often undetectable tumor deposits could serve as a tissue-based marker of residual cancer cells, recurrence risk and chemotherapy resistance.
Published today in Cancer Cell, the comprehensive spatial analyses of CRC metastases used advanced genomic technologies to uncover insights into how micrometastases evolve, evade the immune system and persist after treatment.
The study was co-led by Dipen Maru, M.D., professor of Anatomical Pathology; Scott Kopetz, M.D., Ph.D., professor of Gastrointestinal Medical Oncology and associate vice president for Translational Integration; Linghua Wang, M.D., Ph.D., professor of Genomic Medicine, executive director and head of the Center for Cellular Language Intelligence, associate member of the James P. Allison Institute™, and focus area co-lead with the Institute for Data Science in Oncology; together with co-first authors Yang Liu, Ph.D., postdoctoral fellow of Genomic Medicine, and Akshaya Jadhav, M.D., research scientist in Translational Molecular Pathology.
“These findings provide critical insights into how colorectal cancer cells can hide after treatment and later return, suggesting that tissue-based markers could complement blood-based tests to help identify patients at higher risk of recurrence,” Maru said. “While this gene signature needs validation in larger cohorts to establish clinical efficacy, we are encouraged by the translational relevance of these results.”
What causes colorectal cancer recurrence after treatment?
Colorectal cancer can return when small numbers of cancer cells remain after surgery or chemotherapy, a state known as minimal residual disease (MRD). These cells may shed circulating tumor DNA (ctDNA) into the blood but often cannot be seen with routine imaging.
While ctDNA-based tests can detect signs of MRD, they do not show where residual cancer cells are located or how they survive. This study suggests that colorectal liver micrometastases may offer a window into MRD biology and explains why some patients relapse, even after visible tumors are removed.
The researchers examined 49 tumors from 19 patients with primary CRC, and matched liver and lung metastases. They found that liver micrometastases appeared early in tumor evolution and showed dormant, stem-like features that may allow these microscopic clusters of cancer cells to survive treatment.
How could a six-gene signature help estimate recurrence risk in colorectal cancer?
The researchers compared gene activity in liver micrometastases, larger liver metastases and nearby noncancerous liver tissue. Using high-resolution spatial profiling, they narrowed the findings to six genes that marked a distinct micrometastatic tumor cell state.
Higher levels of this signature, referred to as MicroMetSig-high, were associated with shorter disease-free and MRD-free survival as well as increased risk of recurrence and chemotherapy resistance across several patient datasets.
How do these hidden cells escape immune attack?
Spatial mapping showed that liver micrometastases often were surrounded by immune cells, but many of those cells showed signs of exhaustion, meaning their antitumor activity was weakened. These micrometastases also displayed immune-suppressing signals, including pathways related to PD-1/PD-L1 and other immune checkpoint molecules. The findings suggest these pathways could be explored as future therapeutic targets to reduce recurrence risk.
What does this mean for patients?
The findings may help researchers connect blood-based MRD testing with the hidden tumor deposits that survive treatment. If validated, the six-gene signature could help identify patients who may need closer monitoring or additional treatment after surgery. However, larger studies are needed before the signature can be developed into a clinical test.
“Micrometastases are not simply smaller versions of macrometastases, but rather they appear to represent a distinct biological state,” Wang said. “Using spatial multi-omics and computational analysis, we were able to compare microscopic and larger metastases directly in tissue to help identify programs linked with tumor persistence and disease recurrence. These approaches may help bridge blood-based MRD testing with the tissue biology that drives relapse.”
The researchers noted the need for functional studies to define how micrometastases suppress immune responses and survive treatment to identify ways to target the dormant cancer cells before they cause recurrence.
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The work was supported in part by UT MD Anderson institutional funding, the E.L. and Thelma Gaylord Foundation, the National Cancer Institute of the National Institutes of Health, Charles B. Swank Distinguished Chair, the Andrew Sabin Family Foundation, the Elza A. and Ina Shackelford Freeman Endowed Professorship in Lung Cancer, and the Cancer Prevention and Research Institute of Texas (CPRIT). For a full list of collaborating authors, disclosures and funding sources, see the full paper in Cancer Cell.
These findings provide critical insights into how colorectal cancer cells can hide after treatment and later return, suggesting that tissue-based markers could complement blood-based tests to help identify patients at higher risk of recurrence. While this gene signature needs validation in larger cohorts to establish clinical efficacy, we are encouraged by the translational relevance of these results.