Singapore study uncovers why some colorectal cancer tumors return and spread after chemotherapy

Singapore — A study led by researchers from the A*STAR Genome Institute of Singapore (A*STAR GIS), together with the National Cancer Centre Singapore (NCCS), Singapore General Hospital (SGH), and KU Leuven, Belgium, has uncovered why some colorectal cancer cells become harder to treat and more likely to spread after chemotherapy. Published in Nature Cell Death & Disease, the findings reveal a biological “survival shift” that helps cancer cells withstand treatment and move more aggressively, and point to new ways to identify high-risk patients and potentially improve future treatment strategies.

Summary of Key Findings

1. Some colorectal cancer cells change after chemotherapy, becoming both harder to treat and more likely to spread. This change is linked to high activity of a gene called SERPINE1, which helps drive both drug resistance and metastatic behaviour.
2. In preclinical models, blocking SERPINE1 or the process that activates it improved treatment response, making resistant tumours respond better to commonly used chemotherapy drugs like oxaliplatin.
3. The research team developed a molecular “risk signal” called RESIST-M that can help identify patients more likely to relapse and have poorer treatment outcomes.

Why This Matters

Colorectal cancer affects nearly 1.9 million people worldwide. In Singapore, it is among the most prevalent cancers, with 12,950 new cases reported between 2019 and 2023, according to the Singapore Cancer Registry Annual Report (2023). Chemotherapy remains a standard treatment, but many patients still relapse or develop cancer that spreads to distant organs, which are the leading causes of death from the disease. These challenges are especially pronounced in more aggressive forms of the disease, where commonly used chemotherapy drugs like oxaliplatin often have limited long-term effect.

SERPINE1: The Key Gene Driving Resistance and Cancer Spread

Unlike traditional laboratory models that often use drug doses higher than what patients receive, the research team developed an approach that mimics how chemotherapy is delivered in clinical settings. This allowed them to discover that some cancer cells do not simply survive treatment but change in ways that make them harder to kill and more likely to spread.

The team found that resistant cells alter how they make and use cholesterol, triggering a chain reaction that helps them survive and behave more aggressively. At the centre of this process is SERPINE1, a gene involved in blood coagulation. SERPINE1 becomes highly active in chemotherapy-resistant cancer cells, driving both resistance to the commonly used chemotherapy drug oxaliplatin and traits linked to cancer spread. Higher SERPINE1 activity was also consistently associated with poorer outcomes in patient tumour data, underscoring its relevance to disease progression.

Promisingly, in preclinical models, blocking SERPINE1 or combining oxaliplatin with cholesterol-lowering drugs like statins helped resistant cancer cells respond to treatment again and reduced metastatic behaviour. While these approaches are still at an early stage, they point to actionable directions for future clinical studies focused on preventing disease progression, rather than responding after relapse has occurred.

RESIST-M: A New Molecular Signal to Identify High-Risk Patients

Beyond understanding the biology of resistance, the team also developed a practical tool for clinical use. Building on this discovery, the team developed a nine-gene signature called RESIST-M, which acts as a molecular “risk signal” within a tumour. Across multiple patient datasets, RESIST-M reliably predicted poorer survival and higher relapse risk.

Notably, the signature was especially common in aggressive colorectal cancers classified as CMS4 (consensus molecular subtype 4), including among Singapore patient cohorts. This suggests RESIST-M could help clinicians identify patients at higher risk of cancer relapse and spread, supporting patient stratification and clinical trial design. It could also enable earlier intervention and more targeted follow-up care.

"By understanding how resistance and cancer spread become biologically linked, we were able to identify biomarkers that flag high-risk patients and uncover new intervention strategies. These findings open the door to earlier, more targeted approaches, potentially preventing cancer progression rather than responding after relapse has occurred," said Dr Ramanuj DasGupta, Senior Principal Scientist at A*STAR GIS and senior author of the study.

“Aggressive recurrence remains a challenge for some patients with colorectal cancer. Our findings help explain why this happens and enable earlier identification of higher‑risk patients. The RESIST‑M signature may potentially support more individualised treatment decisions, including repurposing of existing drugs to improve treatment outcomes for this group of patients,” said Professor Iain Tan, Deputy Chairman and Senior Consultant, Division of Medical Oncology, NCCS, and co-author of the study.

Looking Ahead

The research team is proposing clinical trials to evaluate whether targeting SERPINE1 or cholesterol-related pathways, including through existing drugs such as simvastatin, could benefit selected groups of colorectal cancer patients. The team also plans to investigate why cholesterol production decreases in resistant colorectal cancer cells, which could uncover additional therapeutic targets. Ongoing work will also focus on refining RESIST-M as a tool to support patient stratification and clinical trial design.