Colorectal cancer (CRC) is a major contributor to the global burden of disease. CRC tumours are highly heterogeneous with regards to both genetic and epigenetic changes. They form sub-clonal populations as they evolve, with varying metastatic potentials and responses to treatment. At present, we are unable to predict which CRC patients will develop metastatic disease, and how rapidly the disease will progress, resulting in a high unmet clinical need for the development of biomarkers.
While most previous exploration of therapeutic targets and biomarkers have been directed towards proteins, the majority of the transcribed genome comprises non-coding RNA, in particular long non-coding RNAs (lncRNAs). LncRNAs are transcripts of >200 nucleotides in length that do not encode a protein. They have been characterised as oncogenes in many types of cancers, including CRC. LncRNAs are highly suited as biomarkers, due to their superior tissue- and cancer-specific expression compared to protein-coding genes. In order to determine which lncRNAs could be important as biomarkers, we set out to study their expression in the spatial context of the tumour, at near single-cell level. Single-cell expression profiling is superior to bulk RNA sequencing as it better captures lncRNA expression signal, which is cell-type specific and can be lost if expression is only in a small sub-population of cells.
We explored the expression profiles of sub-clonal CRC tumour populations using the 10X Visium Spatial Gene Expression platform. We investigated malignant epithelium compared to adjacent normal epithelium and found a number of lncRNAs that were expressed in tumour sub-populations only. For example, lncRNA-CRC1 was differentially expressed in malignant epithelial cells, but not in adjacent normal tissue. We also investigated the relationship of primary tumour cells with a matched ovarian metastasis and identified the likely seeding population within the primary tumour. Together, these data pave the way for further investigation of potential lncRNA biomarkers and their expression in the spatial context of CRC tumours.