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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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Project description:Background: cancer cells rely on glycolysis as main ATP source (Warbürg effect). Tumor-initiating cells (TICs) are the fraction of cells that give raise and repopulate tumors. TICs are exposed to prolonged periods of oxygen and glucose deprivation (OGD), as they live in a hypoxic niche and they withstand prolonged lack of blood vessels during initial tumorigenesis or metastasis formation (avascular phase). Warbürg effect is energetically inefficient; we hypothesize that TICs might have differential metabolic features. Tumor eradication requires killing TICS; finding such features would have therapeutic implications. Methodology/principal findings: 106 MDA-MB-231 breast-cancer cells (hereafter Wt) were exposed for 5 weeks to 0.2% oxygen and 0.1g/l glucose, recovering 9 clones. Both flow-cytometry (50-fold enrichment in the CD24-/CD44+/CD133+ population) and xenografts in NOD/SCID mice using 100 cells (75% vs. 16% engraftment) suggest that OGD-resistant clones are true TICs (hereafter “TIC clones”). TIC clones showed a 30-fold higher replication and viability (BRDU incorporation, colony assay) than Wt. When exposed to OGD, ATP-production dropped 5-fold in WT, but was maintained in TIC clones by increasing 5-fold the fatty acid and oxygen consumption. These properties were explained by lack of upregulation of HIF-1 alpha and PDK1, as well as an increase in ATP-synthase. Analysis with metabolic inhibitors (2-deoxyglucose, antimycin-A) confirmed glycolysis and mitochondrial respiration as main routes of metabolism for Wt and TIC clones respectively. Metabolomics revealed that glutamine catabolism generated the NADPH required to quench reactive oxygen species generated during mitochondrial respiration in TIC clones. Glutamine deprivation or mitochondrial blockers were able to abrogate the viability of TIC clones. Conclusions/significance: the TIC-fraction of a cancer cell population withstands prolonged OGD by switching from the Warbürg effect to mitochondrial respiration. Targeting this metabolic feature abrogates the survival of TICs.

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

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