Scientists use single-cell techniques to uncover central dichotomy for colorectal cancer cells

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A team of clinician-scientists and scientists, led by A*STAR’s National Cancer Center Singapore (NCCS) and Genome Institute of Singapore (GIS), along with collaborators in Europe and South Korea, used single-cell techniques to uncover a central dichotomy for colorectal cancer. cancer cells, leading to a proposed updated disease classification system. These findings, published in Natural genetics on June 30, 2022, have implications for drug development and treatment approaches for colorectal cancer.

In Singapore and globally, colorectal cancer is one of the most common cancers and the second leading cause of cancer death. As it is a heterogeneous disease with substantial biological and clinical differences between patients, treating colorectal cancer and prescribing individualized treatment to patients driven by the biology of their disease is a challenge. In 2015, clinicians and scientists classified colorectal cancer based on genes expressed by the tumor (transcriptomics) leading to the 2015 International Consensus Molecular Subtype Classification (CMS1-4), which is to date the most robust and widely used transcriptomic system. However, CMS classification relied on transcriptomic analysis of the whole tumor, which meant that individual differences between cancer cells and other stromal cells (e.g., immune cells, fibroblasts, and blood vessels) were obscured and not could not be distinguished.

Current classification systems for colorectal cancer do not sufficiently highlight the molecular basis of the disease. Our team has examined malignant (epithelial) cell subtypes and defined their properties to understand their interactions with other cells using single-cell profiling, so that we can accurately describe colorectal cancer heterogeneity.


Professor Shyam Prabhakar, Co-Lead Author, Associate Director of Space and Single Cell Systems at GIS

The NCCS and GIS-led research team analyzed 373,000 individual cells from 141 tumor samples taken from 63 colorectal cancer patients in Singapore, Belgium and South Korea. Using single-cell and bulk transcriptomics, the team discovered that malignant cells belong to two major epithelial subtypes, which they termed intrinsic consensus molecular subtypes (iCMS), consisting of iCMS2 and iCMS3, finding a central dichotomy that crosses previous classifications of colorectal cancer. Each subtype is characterized by distinct molecular signaling cascades and patterns of DNA duplications or deletions, mutations in key genes, patterns of RNA abundance, and gene regulatory networks.

Colorectal cancer is broadly classified according to two systems, microsatellite unstable colorectal cancer (MSI-H) and microsatellite stable colorectal cancer (MSS). Colorectal cancer with MSI-H is considered highly responsive to immunotherapy whereas MSS cancers are refractory to immunotherapy. Drug development and clinical trials are underway to address this pressing unmet need to find immunotherapies that may work to treat MSS colorectal cancers. However, these trials currently classify MSS colorectal cancer into one group.

The research team found that one-third of MSS tumors were of the iCMS3 subtype and had cancer cells much more similar to MSI cancers than to other MSS cancers. Understanding the similarities between MSI-H cancers and MSS iCMS3 cancers could lead to the identification of components that can be exploited to adapt and modify immunotherapy treatment regimens, which may work better in these patients with similar biology to MSI cancers. -H. Conversely, understanding the distinct biology of iCMS2 MSS cancers could enable the development of targeted drugs focused on this group of colorectal cancers. Moreover, the CMS4 group of colorectal cancers, known to have the highest tendency to metastasize, was also divided into iCMS2 and iCMS3 subtypes. Between these two groups, CMS4 cancers with iCMS3 epithelial cells were found to have the worst prognosis.

Based on their findings, the research team proposed a refinement of the CMS classification known as “IMF”, which groups colorectal cancer into five groups based on their epithelial status, microsatellite status and the presence of fibrosis. The classification proposed by the IMF provides new information on colorectal cancer and its origin, course and response to treatment. Further preclinical and clinical studies on the biology of the five groups could inform prevention, diagnosis and therapy.

“Currently, clinical trials are focused on using immunotherapy combinations to treat stable microsatellite colorectal cancers as a single group, disregarding the differences between stable microsatellite colorectal cancers. Our study changes the understanding of the diversity of the colorectal cancer by showing that there are fundamentally different biological subsets with distinct epithelial characteristics, microsatellite status, and interactions with fibrosis.This could help inform a targeted strategy of drug development efforts to effectively target these different subsets of colorectal cancer,” said co-senior author Associate Professor Iain Tan, Senior Consultant and Research Director, Division of Medical Oncology, NCCS.

The research team plans to perform further analyzes to characterize the biological properties, interactions, and drug response of iCMS2 and iCMS3 cells, and also to reanalyze clinical trial data to identify differences in treatment response between these two types of cancer.

Source:

Journal reference:

Joanito, I., et al. (2022) Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer. Natural genetics. doi.org/10.1038/s41588-022-01100-4.

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