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Dynamics of cancer cell subpopulations in primary and metastatic colorectal tumors.

ABSTRACT: Intratumor heterogeneity-heterogeneity of cancer cells within a single tumor-is considered one of the most problematic factors of treatment. Genetic heterogeneity, such as in somatic mutations and chromosome aberrations, is a common characteristic of human solid tumors and is probably the basis of biological heterogeneity. Using mutations in APC, TP53 and KRAS as markers to identify distinct colorectal cancer subpopulations, we analyzed a total of 42 primary colorectal cancer tissues and six paired liver metastases with multipoint microsampling, which enabled analysis of mutation patterns and allelic imbalances with a resolution of 0.01 mm(2) (about 200 cells). There was usually more than one subpopulation in each primary tumor. Only two of 15 (13.3%) cases with three gene mutations and eight of 27 (29.6%) cases with two gene mutations had a single subpopulation. Cells with mutations in all of the examined genes usually constituted the major population. Multipoint microsampling of six primary and metastatic tumor pairs revealed that the majority of discrepancies in mutation patterns found with the bulk tissue analysis were due to loss of subpopulations in the metastatic tissues. In addition, multipoint microsampling uncovered substantial changes in subpopulations that were not detected with bulk tissue analysis. Specifically, the proportion of KRAS mutation-negative subpopulations increased in the metastatic tumors of four cases. Because KRAS mutation status is linked to cetuximab/panitumumab efficacy, subpopulation dynamics could lead to differences in response to cetuximab/panitumumab in primary versus metastatic tumors.

SUBMITTER: Goranova TE

PROVIDER: S-EPMC3081061 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundColorectal 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.

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Dynamics of cancer cell subpopulations in primary and metastatic colorectal tumors.

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