Researchers at The University of Texas MD Anderson Cancer Center announced on July 9 the identification of a six-gene signature in microscopic colorectal cancer liver metastases that may help predict recurrence after treatment. The findings suggest these small, often undetectable tumor deposits could serve as a tissue-based marker for residual cancer cells, recurrence risk, and chemotherapy resistance.
The study, published in Cancer Cell, involved comprehensive spatial analyses of colorectal cancer metastases using advanced genomic technologies to understand how micrometastases evolve, evade the immune system, and persist after treatment. The research 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 and executive director at the Center for Cellular Language Intelligence; along with co-first authors Yang Liu, Ph.D., postdoctoral fellow in Genomic Medicine, and Akshaya Jadhav, M.D., research scientist in Translational Molecular Pathology.
Colorectal cancer can recur when minimal residual disease remains after surgery or chemotherapy. These cells may release circulating tumor DNA into the blood but are often invisible to routine imaging. While blood-based tests can detect signs of minimal residual disease (MRD), they do not indicate where residual cells are located or how they survive. The researchers said their study suggests that liver micrometastases provide insight into MRD biology and may explain why some patients relapse even after visible tumors are removed.
The team examined 49 tumors from 19 patients with primary colorectal cancer and matched liver and lung metastases. They found that liver micrometastases appeared early during tumor evolution and displayed dormant stem-like features that might allow these clusters to survive treatment. High-resolution spatial profiling narrowed their findings to six genes marking a distinct micrometastatic cell state—higher levels of this signature were associated with shorter disease-free survival as well as increased risk of recurrence and chemotherapy resistance across multiple patient datasets.
Spatial mapping showed many micrometastases were surrounded by immune cells exhibiting signs of exhaustion—meaning weakened antitumor activity—and also displayed immune-suppressing signals related to PD-1/PD-L1 pathways. The researchers said these pathways could be explored as future therapeutic targets to reduce recurrence risk.
“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 that larger studies are needed before this six-gene signature can be developed into a clinical test.
