Mapping Single-Cell Genomic, Transcriptomic Landscapes of Colorectal Cancer

Using a variety of sequencing techniques, scientists from Peking University have generated maps of the single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer (CRC). The work, which appears in this week's Genome Medicine, sheds new light on the molecular mechanisms underlying the disease. While technological advances have enabled studies into the cellular and molecular basis of CRC carcinogenesis and metastasis, intratumoral heterogeneities and relationships among different omics of the cancer have not been systematically investigated. To do so, the researchers performed whole genome sequencing, multi-region whole exome sequencing, simultaneous single-cell RNA-sequencing, and single-cell targeted cDNA Sanger sequencing on matching adjacent normal tissues, primary tumors, and metastatic tumors from 12 metastatic CRC patients. The PPAR signaling pathway, they find, is prevalently and aberrantly activated in CRC tumors. Further, in patient-derived tumor organoids, blocking this pathway suppressed the growth and promoted the apoptosis of CRC, suggesting that aberrant activation of the PPAR signaling pathway plays a critical role in CRC tumorigenesis. The investigators also combined single-cell RNA-seq and single-cell point mutation identification by targeted cDNA Sanger sequencing to uncover phenotypic differences between cancer cells with and without critical point mutations in the same patient in vivo at single-cell resolution. The work, the study's authors write, offers "novel knowledge on metastatic mechanisms, as well as potential markers and therapeutic targets for CRC diagnosis and therapy."