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Disseminated tumor cell of colorectal cancer adopt the wound healing program of epidermal keratinocyte [scRNA-seq]

ABSTRACT: Disseminated tumor cells (DTCs) are a critical cell population in the metastasis process, and understanding their features is essential for the development of cancer treatment. We show that DTCs of colorectal cancer (CRC) transiently adopted the cellular state resembling to the activated epidermal keratinocyte during wound healing. Using the orthotropic transplantation of patient derived organoids (PDOs), we demonstrated that collective migrating cell clusters in primary site did not contain cancer stem cells but contained cells expressing wound-inducible keratins. Mechanistically, inhibition of EZH2 methyltransferase and activation of YAP signaling synergistically promoted DTC phenotype and potentiated dissemination to the distant organs. Collectively, these observations demonstrated that CRC cells alter the cellular hierarchy and adopt re-epithelization program resembling to the tissue repair process to generate DTCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270767 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:The aim of this study was to establish a single-cell array comparative genomic hybridization (SCaCGH) method providing in-depth genomic analysis of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs). The robustness and resolution limits of the method were estimated with different cell amounts of the breast cancer cell line SKBR3 using 44k and 244k arrays. Subsequent adjustments of the method were conducted analyzing the copy number profiles of 28 CTCs in combination with four hematopoietic cell (HC) controls from eight metastatic patients and of 24 DTCs, three probable HCs, and five HC controls from seven breast cancer patients and one healthy donor. The frequency of the major genomic gains and losses of the analyzed DTC revealed similarities to primary breast tumor samples with some evident differences. Three of the patients had available profiles for DTC and the corresponding primary tumor. In 2/3 of the examined DTCs, equivalent genomic changes and common aberration breakpoints were disclosed, both to each other and to the corresponding primary tumors. Interestingly, similar copy number changes were found in DTCs taken at time of diagnosis or in DTCs collected at 3-years relapse-free follow up. Residual immunomorphological characterized tumor cells showed balanced profiles with only minor aberrations. Three cells with unclear morphological identification showed either balanced profiles (n=2) or aberrations comparable to the primary tumor and DTC (n=1). SCaCGH may be a powerful tool for molecular characterisation of immunostained and morphological identified CTCs and DTCs to explore the malignant potential, therapeutic targets and tumor heterogeneity of single tumor cells. 24 DTCs, 3 probable HCs, and 5 HCs from 7 early-stage breast cancer patients, 28 CTCs and 4 HCs from 8 metastatic breast cancer patients, and 1 healthy donor were analysed. Comparison with the primary tumor was done in 3 patients. The reference for the patients was DNA from multiple anonymous female donors. This submission does not include the SKBR3 data obtained from the 44k array.

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Disseminated tumor cell of colorectal cancer adopt the wound healing program of epidermal keratinocyte [scRNA-seq]

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