Researchers at the University of Texas MD Anderson Cancer Center have identified six genetic signatures in microscopic colorectal cancer (CRC) liver metastases that may help predict recurrence after treatment. This finding suggests that these small, often undetectable tumor deposits may serve as tissue-based markers of residual cancer cells, recurrence risk, and chemotherapy resistance.
Published today is cancer cellsa comprehensive spatial analysis of CRC metastases used advanced genomic techniques to uncover insights into how micrometastases evolve, evade the immune system, and persist after treatment.
The study was co-led by Dipen Mal, MD, professor of anatomic pathology. Scott Kopetz, MD, Professor of Gastrointestinal Oncology and Vice President of Translational Integration. Linghua Wang, MD, Ph.D., Professor of Genomic Medicine, Executive Director and Director of the Center for Cellular and Linguistic Intelligence, Associate Member of the James P. Allison Institute™, and Co-Leader of Focus Areas with the Oncology Data Science Institute. We will conduct joint research with co-lead authors Dr. Yang Liu (postdoctoral researcher in genomic medicine) and Akshaya Jadhav, MD (researcher in translational molecular pathology).
These findings provide important insight into how colorectal cancer cells hide after treatment and subsequently recur, and suggest that tissue-based markers may complement blood-based tests to help identify patients at high risk of recurrence. Although this genetic signature needs to be validated in larger cohorts to establish clinical efficacy, we are encouraged by the translational relevance of these results. ”
Dipen Mal, MD, Professor of Anatomical Pathology, University of Texas MD Anderson Cancer Center
What causes colorectal cancer to recur after treatment?
Colorectal cancer can recur if a small number of cancer cells remain after surgery or chemotherapy, a condition known as minimal residual disease (MRD). These cells can release circulating tumor DNA (ctDNA) into the bloodstream, which is often invisible to routine imaging.
Although ctDNA-based tests can detect signs of MRD, they do not tell us where the remaining cancer cells are or how they are surviving. This study suggests that colorectal liver micrometastases may provide a clue into MRD biology and explains why some patients relapse even after removing visible tumor.
Researchers examined 49 tumors from 19 patients with primary colorectal cancer and found that liver and lung metastases were consistent. They found that liver micrometastases appear early in tumor evolution and exhibit dormant, stem-like features that allow these tiny clusters of cancer cells to survive treatment.
How can a six-gene signature help estimate the risk of colorectal cancer recurrence?
The researchers compared gene activity in liver micrometastases, larger liver metastases, and nearby non-cancerous liver tissue. Using high-resolution spatial profiling, they narrowed their results down to six genes that characterize the apparent micrometastatic tumor cell state.
High levels of this signature, called MicroMetSig-high, were associated with shorter disease-free and MRD disease-free survival, as well as increased risk of recurrence and chemoresistance across several patient datasets.
How do these hidden cells evade immune attack?
Spatial mapping shows that liver micrometastases are often surrounded by immune cells, many of which show signs of fatigue, meaning their antitumor activity is diminished. These micrometastases also exhibited immunosuppressive signals, including pathways associated with PD-1/PD-L1 and other immune checkpoint molecules. This finding suggests that these pathways may be investigated as future therapeutic targets to reduce the risk of relapse.
What does this mean for patients?
The discovery could help researchers link blood-based MRD tests to hidden tumor deposits that survive treatment. If the six-gene signature is validated, it could help identify patients who need close monitoring or additional treatment after surgery. However, larger studies are needed to develop the signature into clinical testing.
“Micrometastasis appears to represent a distinct biological condition rather than simply a smaller version of macrometastasis,” Wang said. “Using spatial multi-omics and computational analysis, we were able to directly compare microscopic and larger metastases within tissues, helping to identify programs associated with tumor persistence and disease recurrence. These approaches may help bridge blood-based MRD testing and the tissue biology that drives recurrence.”
The researchers pointed to the need for functional studies to determine how micrometastases suppress immune responses and resist treatment to identify ways to target dormant cancer cells before they cause recurrence.
sauce:
University of Texas MD Anderson Cancer Center
References:
Ryu, Y. Others. (2026). Spatial multi-omics landscape of macrometastasis and micrometastasis in colorectal cancer. cancer cells. DOI: 10.1016/j.ccell.2026.06.009. http://www.cell.com/cancer-cell/fulltext/S1535-6108(26)00296-5
