We’re heralding a new era of precision cancer care; a transformative change driven by gene-profiling technologies is slowly phasing out one-size-fits-all standard treatments such as chemotherapy.
Designing personalised treatment protocols for colorectal cancer (CRC) patients currently relies on a consensus molecular subtype (CMS) classifier, a system used to categorise tumours based on their genetic and molecular characteristics.
However, researchers say that because CMS analyses tumour cells in bulk, it lacks resolution. Today’s CMS can be compared to classifying cars into broad categories such as ‘sports cars’ or ‘utility vehicles’, which overlooks the unique features and capabilities of individual models.
Iain Tan, a Principal Investigator at A*STAR’s Genome Institute of Singapore (GIS), said that single-cell RNA sequencing (scRNA-seq) technologies can help to fill the gap. “We can identify malignant cell subtypes and their properties, as well as understand their interactions with other cells in the tumour microenvironment,” said Tan, adding that this provides a clearer view of CRC heterogeneity.
Tan was part of a cross-functional team including researchers from National Cancer Centre, Singapore General Hospital, and experts from Singapore, Switzerland, Belgium, Korea and the US that aimed to revamp the current CMS with the help of transcriptomics.
The team analysed a massive 370,000 transcriptomes from 63 patients across five cohorts, generating one of the largest single-cell CRC datasets to date. A subset of about 50,000 epithelial cell transcripts formed the nexus of their inquiry, as these cells are known to be the origin of most CRCs.
Their analyses revealed that malignant epithelial cells were divided into two intrinsic-molecular subtypes—iCMS2 and iCMS3—characterised by distinct signalling pathways and mutational profiles. They also found that one-third of microsatellite stable tumours share more in common with microsatellite instability-high tumours in terms of their genetic activity and biological pathways—a finding that challenges the traditional classifications of CRC.
With this, the existing CMS went from four broad categories to five distinct subtypes, which now include data on the tumour’s intrinsic epithelial subtype, microsatellite instability status and fibrosis.
In addition, the researchers offered trailblazing insights on the existing classifier, CMS4, known to represent fibrotic tumours that are particularly prone to post-treatment relapse.
“CMS4 tumours are evenly split between iCMS2 and iCMS3, [and are] not a distinct subgroup,” explained Tan. “CMS4 cancers with iCMS3 epithelium have particularly poor outcomes.”
These new frameworks to stratify CMS4 tumours provide a more nuanced understanding that can reshape diagnostic and treatment strategies for CRC patients. For example, iCMS3 cancers have an inflammatory and immune-activated tumour microenvironment and may therefore be more susceptible to immunotherapies.
Moving ahead, the researchers’ ongoing pursuits are exploring the early development and immunological makeup of iCMS2 and iCMS3 tumours. “We are also performing biological and clinical studies to prevent CRC metastasis,” concluded Tan.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS) and the Institute of Molecular and Cell Biology (IMCB).
