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MMP14 empowers tumor-initiating breast cancer cells under hypoxic nutrient-depleted conditions

ABSTRACT: Tumor-initiating cells (TICs) exist in breast cancer and are thought to be the cause of tumor initiation, progression, and relapse. In these processes, proteases play an important role. Additionally, conditions of the tumor milieu, including hypoxic nutrient-deprived as well as normoxic nutrient-rich environments, influence the tumor-promoting actions of neoplastic cells. Therefore, we investigated the role of proteases in TICs and their response to different environments by means of a generated immortalized TIC line. After assessing immortalized TIC tumorigenicity by limiting dilution assays in vivo and their characteristics in different environmental conditions, a transcriptome analysis was performed of iTICS cultured in hypoxic stem cell conditions and 1-7 days in normoxic standard condtitions. A high proteolytic signature was identified and further investigated by inhibitor treatment and shRNA mediated RNA interference of Mmp14.

ORGANISM(S): Mus musculus

PROVIDER: GSE113826 | GEO | 2018/11/27

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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MMP14 empowers tumor-initiating breast cancer cells under hypoxic nutrient-depleted conditions

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