Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors

Abstract

Background Colorectal cancer (CRC) ranks as the second-leading cause of cancer-related death worldwide with metastases being the main cause of cancer-related death. Here, we investigated the genomic and transcriptomic alterations in matching adjacent normal tissues, primary tumors, and metastatic tumors of CRC patients. Methods We performed whole genome sequencing (WGS), multi-region whole exome sequencing (WES), simultaneous single-cell RNA-Seq, and single-cell targeted cDNA Sanger sequencing on matching adjacent normal tissues, primary tumors, and metastatic tumors from 12 metastatic colorectal cancer patients (n=84 for genomes, n=81 for exomes, n=9120 for single cells). Patient-derived tumor organoids were used to estimate the anti-tumor effects of a PPAR inhibitor, and self-renewal and differentiation ability of stem cell-like tumor cells. Results We found that the PPAR signaling pathway was prevalently and aberrantly activated in CRC tumors. Blocking of PPAR pathway both suppressed the growth and promoted the apoptosis of CRC organoids in vitro, indicating that aberrant activation of the PPAR signaling pathway plays a critical role in CRC tumorigenesis. Using matched samples from the same patient, distinct origins of the metastasized tumors between lymph node and liver were revealed, which was further verified by both copy number variation and mitochondrial mutation profiles at single-cell resolution. By combining single-cell RNA-Seq and single-cell point mutation identification by targeted cDNA Sanger sequencing, we revealed important phenotypic differences between cancer cells with and without critical point mutations (KRAS and TP53) in the same patient in vivo at single-cell resolution. Conclusions Our data provides deep insights into how driver mutations interfere with the transcriptomic state of cancer cells in vivo at a single-cell resolution. Our findings offer novel knowledge on metastatic mechanisms as well as potential markers and therapeutic targets for CRC diagnosis and therapy. The high-precision single-cell RNA-seq dataset of matched adjacent normal tissues, primary tumors, and metastases from CRCs may serve as a rich resource for further studies.

Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond

“…Other tools that could help improve personalized medicine include the triphasic enhanced computed tomography radiomics signature that was recently tested by Cao et al [ 238 ] and has been shown to be effective in predicting CRC MSI status with 0.837 and 0.821 accuracy and sensitivity, respectively. Moreover, whole genome sequencing, multi-region whole exome sequencing, simultaneous single-cell RNA-sequencing, and single-cell targeted cDNA Sanger sequencing are being used to obtain single-cell genomic and transcriptomic landscapes of adjacent normal tissues, primary tumors, and metastatic tumors[ 239 ], which could also improve individualized treatment.…”

Unsupervised reference-free inference reveals unrecognized regulated transcriptomic complexity in human single cells

“…Mitochondrial genes also had high diversity, highest in an anchor with compactors mapping to MT-ND5 , with 24 compactors in donor 1 lung, the greatest number of compactors generated in a single donor-tissue (Table 3) by any anchor with compactors mapping to an annotated gene. MT-ND5 is a component of the transmembrane electron transport chain in mitochondria with previously reported recurrent mutations with clinical significance (Jaberi et al 2020; Wang et al 2022).…”

Role of hypoxia-inducible factor-1α and survivin in breast cancer recurrence and prognosis

“…GO analysis revealed that HIF1A and BIRC5 are involved in pathways associated with carcinogenesis. These signaling pathways cause activation of the intracellular segment of the cell surface receptor, which transduces extracellular signals into the cell [ 26 , 27 ]. Therefore, the use of inhibitors of the HIF1A and BIRC5 pathways may be considered in the future to control tumor growth.…”