Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3
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ABSTRACT:
PROVIDER: PRJNA545250 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancer stem cells (BCSCs) are unique in their ability to undergo unlimited self-renewal, an essential process in breast cancer recurrence following metastatic dormancy. Emergent metastatic lesions were subjected to microarray analysis, which identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) as a differentially expressed gene coupled to metastatic recurrence. Here, we report that elevated Pfkfb3 expression correlates with the appearance of aggressive breast cancers and reduces relapse-free survival, as well as enhances BCSC self-renewal and metastatic outgrowth. We observe an inverse relationship between Pfkfb3 expression and autophagy, which reduces Pfkfb3 expression and elicits cellular dormancy. Targeted depletion of Atg3, Atg7, or p62/sequestosome-1 to inactivate autophagy restores aberrant Pfkfb3 expression in dormant BCSCs, leading to their reactivation of proliferative programs and outgrowth. Moreover, Pfkfb3 interacts physically with autophagy machinery, specifically the UBA domain of p62/sequestosome-1. Importantly, disrupting autophagy and this event enables Pfkfb3 to drive dormant BCSCs and metastatic lesions to recur.
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Project description:Transcriptome analysis of formalin fixed paraffin embedded murine lung tumors
2019-05-30 | GSE131890 | GEO
Project description:Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key molecule of glucose metabolism in cytoplasm, was found in various tumors. Emerging evidence suggested that PFKFB3 also located in nucleus and shown regulatory functions other than glycolysis. In this study, we found that PFKFB3 expression is associated with hepatocellular carcinoma (HCC) growth and mainly located in the nucleus of tumor cells. PFKFB3 overexpression was associated with large tumor size, and poor survival of patients with HCC. Knockdown of PFKFB3 inhibited HCC growth, not only by reducing glucose consuming but also damaging DNA repair function leading to G2/M phase arrest and apoptosis. Therefore, we performed a cDNA microarray in PFKFB3 knockdown SMMC7721 cells.
2018-03-01 | GSE106603 | GEO
Project description:We hypothesized that PFKFB3 inhibits fructose metabolism in pulmonary microvascular endothelial cells (PMVECs) and found that PFKFB3 knockout cells survive better than wild type cells in fructose-rich media, more so under hypoxia. Our findings indicate that PFKFB3 is a molecular switch that controls glucose versus fructose utilization in glycolysis and help to better understand lung endothelial cell metabolism during respiratory failure.
2023-08-01 | GSE230660 | GEO
Project description:Analysis of gene expression profiles upon PFKFB3 under- or overexpression during inhibition or activation of notch signaling. With this experiment we aimed to identify whether alterations in PFKFB3 could influence the expression pattern of angiogenic genes in conditions that favor a tip- or stalk cell gene signature. Total RNA was collected of human umbilical vein endothelial cells either under- or overexpressing PFKFB3 and/ or have inhibited or activated notch signaling respectively. Cells were harvested 48h after manipulation of PFKFB3 and notch levels.
2013-08-01 | E-GEOD-45750 | biostudies-arrayexpress
Project description:Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging4-8. Our new data identifies Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits Wnt5A, enabling efficient metastatic outgrowth. Further, we have identified the tyrosine kinase receptors AXL and MER as promoting a dormancy-toreactivation axis respectively. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung.
2022-03-03 | MSV000088977 | MassIVE
Project description:Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) by targeting endothelial cells (ECs) is emerging as anti-cancer treatment. Here, we show that tumor ECs (TECs) have a hyper-glycolytic metabolism, shunting glycolytic intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell intra- and extravasation and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs and rendering glycolytic pericytes more quiescent; it also lowered the expression of cancer cell adhesion molecules in ECs. Additionally, PFKFB3-blockade treatment improved chemotherapy. Considering TEC metabolism for anti-cancer treatment might thus merit further attention.
2016-11-17 | E-MTAB-4842 | biostudies-arrayexpress
Project description:Solid cancers frequently relapse with distant metastasis, despite local and systemic treatment. Cellular dormancy has been identified as an important mechanism underlying drug resistance enabling late relapse. Therefore, relapse from invisible, minimal residual cancer of seemingly disease-free patients call for in vitro models of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERKlow:P-p38high dormancy signaling ratio, along with Ki67− expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domain 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 down-regulation. Thus, our biomaterial-based approach will enable systematic screens for previously unidentified compounds suited to eradicate potentially relapsing dormant cancer cells.
2024-08-21 | GSE182606 | GEO
Project description:To investigate the functional role of PFKFB3 in VSMCs osteogenic differentiation, we knockdowned PFKFB3 expression in VSMCs using siRNAs
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Project description:Protein aggregates occur in all living cells due to misfolding of proteins. In bacteria, protein aggregation is associated with cellular inactivity, which is related to dormancy and tolerance to stressful conditions, including the exposure to antibiotics. In Escherichia coli, the membrane toxin TisB is an important factor for dormancy and antibiotic tolerance upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin. Here, we show that TisB provokes protein aggregation in response to ciprofloxacin. The stress response and TisB-dependent protein aggregates are analyzed by LC-MS.
2024-10-04 | PXD049478 | Pride