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P140Cap overexpression in Balb-neuT HER2 breast cancer transgenic mice

ABSTRACT: In HER2-positive breast cancer patients the adaptor protein p140Cap correlates with increased patient survival and decreased probability to develop metastasis. Causally, p140Cap negatively regulates in vitro and in vivo breast tumor properties. Here we show that p140Cap status correlates with a rewiring of the tumor immune microenvironment, with an increased presence of tumor-infiltrating lymphocytes (TILs) in human breast cancers and an inverse correlation with inflammatory hallmarks. Preclinical syngeneic p140Cap models show a significant increase of CD8+ T-Lymphocytes, NK cells and M1-macrophages in p140Cap tumors, a reduced mobilization and a decreased recruitment of G-CSF-dependent Myeloid-Derived Suppressor Cells (MDSC), with a specific reduction in G-CSF mRNA and protein levels. Indeed, p140Cap impacts on the G-CSF axis by reducing the fraction of Tumour-Initiating Cells (TICs) that exhibit an enhanced G-CSF production. Interestingly, p140Cap affects the TIC compartment by limiting the active β-Catenin intracellular pool, stabilizing the destruction complex. These findings identify a novel role of p140Cap in preventing the development of an immunosuppressive tumor promoting microenvironment in Breast Cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE176229 | GEO | 2022/12/19

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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P140Cap overexpression in Balb-neuT HER2 breast cancer transgenic mice

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