Genomics

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Proteolysis - hallmark of tumor-initiating cells in polyoma-middle-T-oncogene induced murine mammary carcinomas.


ABSTRACT: Tumor initiating cells (TIC) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potency, TICs are important for metastasis formation and involved in chemotherapy resistance. Here we explored the molecular pathways that enable the tumor initiating potential of a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45-, revealed a high tumorigenicity compared to CD24-CD90- cancer cells in colony formation assays as well as upon orthotopic transplantation into the mammary fad pad of mice. In addition, these orthotropically grown CD24+CD90+ TICs metastasized to the lungs. Upon cell sorting from primary tumors the transcriptome of TICs was compared with that of CD24-CD90- cancer cells by RNAseq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in CD24+CD90+TICs. Accordingly, TICs showed a high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on the colony morphology in 3D cell culture assays. Proteases have been frequently implicated in tumor growth and progression by shaping the extracellular environment and liberating growth factors, cytokines and chemokines. We conclude that CD24+CD90+ cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature that is likely to represent a functional hallmark of metastatic TICs of mammary carcinomas.

ORGANISM(S): Mus musculus

PROVIDER: GSE75946 | GEO | 2016/08/17

SECONDARY ACCESSION(S): PRJNA305759

REPOSITORIES: GEO

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