Treating cancer with chemotherapy can be like spraying weedkiller on a crop field. By blanketing the landscape, both treatments aim to destroy every trace of their targets. However, just as a few tough weeds might survive the blast, some cancer cells can escape, becoming not only treatment-resistant but also more aggressive in spreading (metastasising).
That’s an issue faced today with oxaliplatin, a long-time standard chemotherapy for colorectal cancer (CRC). While the drug has benefited many patients, some benefit much less than others for reasons that remain unclear, noted Mohua Das, a Scientist at the A*STAR Genome Institute of Singapore (A*STAR GIS).
“We need reliable models of metastasis driven by chemotherapy resistance, which can simulate what happens in patients whose tumours don’t respond to oxaliplatin—or chemotherapy in general—and eventually spread,” said Das, who is also a senior postdoctoral fellow at the laboratory of Ramanuj DasGupta, A*STAR GIS Senior Principal Scientist. “These would help us uncover the biological ‘control switches’ linking drug resistance with metastasis, which could in turn help us identify patients likely to benefit from existing therapies, and develop new therapies.”
To this end, Das and Stephen Wong, a former graduate student at the DasGupta laboratory, recently co-led the development and transcriptomic analysis of a laboratory model for acquired oxaliplatin resistance in CRC. The team included A*STAR GIS colleagues such as Jiamin Loo, and research partners such as Iain Tan and colleagues from the National Cancer Centre Singapore; Experimental Drug Development Centre, Singapore; University of Geneva, Switzerland; and Katholieke Universiteit Leuven, Belgium.
The team first treated CRC cells with repeated cycles of oxaliplatin over time, closely mimicking the treatment regimes received by patients with CRC. Using bulk and single-cell technologies to analyse changes in gene activity, the team then examined how the surviving cancer cells adapted.
“We found that CRC cells progressively switch on specific gene programmes as they become resistant,” said DasGupta. “Through computational analyses and experimental validation, we identified the gene SERPINE1 as the most prominent and targetable factor within these programmes, driving both chemotherapy resistance and metastatic behaviour.”
Based on their discovery, the team performed drug screens to identify novel SERPINE1-inhibiting treatments, validating their ability to stall metastasis in mouse models. They also developed a composite multi-gene signature, RESIST-M, and evaluated its ability to stratify independent CRC patient cohorts.
“RESIST-M consistently predicted poorer overall and recurrence-free survival, and was enriched in aggressive, fibrotic tumour subtypes, supporting its potential utility for patient stratification,” said Das. “Identifying high-risk patients earlier based on RESIST-M status could help clinicians make more informed therapy selections, ultimately improving treatment outcomes and life expectancy.”
In collaboration with the Chinese University of Hong Kong, the team is investigating anti-PD-L1 resistance in liver cancer, with results so far consistent with their oxaliplatin resistance models. “This suggests SERPINE1 may mediate a broader, therapy-agnostic mechanism of cellular resistance across both chemotherapeutic and immunotherapeutic contexts,” DasGupta added.
The A*STAR researchers contributing to this research are from the A*STAR Genome Institute of Singapore (A*STAR GIS).
