Enhancement of melanoma aggressiveness via p38-MAPK, HIF-1α pathways, and metabolic reprogramming induced by Candida albicans
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ORGANISM(S): Mus musculus
PROVIDER: GSE285124 | GEO | 2025/10/16
REPOSITORIES: GEO
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Project description:Increased levels of hypoxia and hypoxia inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged anti-angiogenic therapy of tumors can delay tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene set enrichment analysis of microarrays from pre-treatment biopsies found the Gene Ontology category “Response to hypoxia” was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. We thus examined Dox treatment in 4 sarcoma cell lines, and found Dox at low concentrations (1-10 uM) blocked HIF-1α induction of VEGF-A by 84-97%, while inhibition of other HIF-1α-target genes including CA9, c-Met and FOXM1 was variable. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 and metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, primarily via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α-target genes which may promote resistance to anti-angiogenic and other therapies. Metronomic Dox can block HIF-1α activation of target genes and works synergistically with anti-VEGF therapy to inhibit sarcomas. Pre-treatment biopsies were collected from 16 human sarcoma. The gene expression analysis was performed using Illumina platform.
2011-08-29 | E-GEOD-31715 | biostudies-arrayexpress
Project description:Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide. Gut microbiota, including fungal species, are increasingly implicated in CRC progression, while the molecular mechanisms underlying host-fungal interactions in this context remain poorly understood. Here, we show that Candida albicans (C. albicans) activates pro-metastatic signaling pathways, MAPK and NF-κB, leading to upregulation of oncogenic transcription factors c-Jun and c-Myc. This cascade stabilizes and activates hypoxia-inducible factor 1α (HIF-1α), a central regulator of tumor metabolic reprogramming and angiogenesis, ultimately fostering a pro-tumorigenic microenvironment. Mechanistically, we identify candidalysin, a secreted peptide toxin of C. albicans, as a critical effector that engages epidermal growth factor receptor (EGFR) and toll-like receptor 2 (TLR2) in a species- and cancer cell type-dependent manner. These findings are further supported by patient-derived colonic organoids. Collectively, our study delineates a C. albicans-EGFR/TLR2-ERK/NF-κB-HIF-1α axis that promotes hypoxia-like responses in CRC, revealing a previously underappreciated role of fungal pathogens in shaping the tumor microenvironment and offering potential targets for therapeutic interventions.
2025-08-16 | GSE279572 | GEO
Project description:In primary melanoma, the amount of VEGF-C expression and lymphangiogenesis predict the probability of metastasis to sentinel nodes, but conditions boosting VEGF-C expression in melanoma are poorly characterized. By comparative mRNA expression analysis of a set of 22 human melanoma cell lines, we found a striking negative correlation between VEGF-C and MITF expression, which was confirmed by data mining in GEO databases of human melanoma Affymetrix arrays. Moreover, in human patients, high VEGF-C, and low MITF levels in primary melanoma significantly correlated with the chance of metastasis. Pathway analysis disclosed the respective JNK- and p38/MAPK activities as being responsible for the inverse regulation of VEGF-C and MITF. Predominant JNK signaling results in a VEGF-Clow/MITFhigh phenotype, these melanoma cells are highly proliferative, show low mobility and are poorly lymphangiogenic. Predominant p38 signaling results in a VEGF-Chigh/MITFlow phenotype, corresponding to a slowly cycling, highly mobile, lymphangiogenic and metastatic melanoma.
2015-10-01 | GSE71122 | GEO
Project description:Background: Tibetan chicken, a unique plateau breed, has a suite of adaptive features that enable it to tolerate the high-altitude hypoxic environment. HIF‐1α (hypoxia inducible factor 1 subunit alpha) is a crucial mediator of the cellular response to hypoxia. HIF‐1α maintains oxygen homeostasis by inducing glycolysis, erythropoiesis, and angiogenesis; however, the target genes involved in adaptive responses to hypoxia in animals and birds of plateaus are still unclear. Results: We used ChIP-seq to map HIF‐1α binding regions in chorioallantoic membrane (CAM) tissue of chicken embryos, and identified 752 HIF-1α target genes (TG), of which 112 were differentially expressed target genes (DTGs) between the two breeds. We found that eight genes (PTK2, GPNMB, CALD1, SLC25A1, SPRY2, NUPL2, RANBPL, and CBWD1) play important roles in hypoxic adaption by regulating blood vessel development, energy metabolism through angiogenesis, vascular smooth muscle contraction, and various hypoxia-related signaling pathways (including VEGF and MAPK) in Tibetan chickens during embryonic development. Conclusions: This study enhances our understanding of the molecular mechanisms of hypoxic adaptation in Tibetan chickens and provides new insights into adaptation to hypoxia in humans and other species living at high altitude.
2019-09-12 | GSE137302 | GEO
Project description:Increased levels of hypoxia and hypoxia inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged anti-angiogenic therapy of tumors can delay tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene set enrichment analysis of microarrays from pre-treatment biopsies found the Gene Ontology category “Response to hypoxia” was upregulated in poor responders, and hierarchical clustering based on 140 hypoxia-responsive genes separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. We thus examined Dox treatment in 4 sarcoma cell lines, and found Dox at low concentrations (1-10 uM) blocked HIF-1α induction of VEGF-A by 84-97%, while inhibition of other HIF-1α-target genes including CA9, c-Met and FOXM1 was variable. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 and metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, primarily via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α-target genes which may promote resistance to anti-angiogenic and other therapies. Metronomic Dox can block HIF-1α activation of target genes and works synergistically with anti-VEGF therapy to inhibit sarcomas.
2011-08-30 | GSE31715 | GEO
Project description:Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae that leads to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from hematogenous source into the brain across the blood-brain barrier (BBB); the mechanisms however are still poorly understood. Current treatment strategies include adjuvant dexamethasone therapy for cerebral edema, the prime reason for neurological complications and mortality, which is followed up by antibiotics. The success of corticosteroids is however inconclusive, necessitating the development of new therapies for controlling cerebral edema. We have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we therefore hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is critically involved in the transmigration of pathogens across the BBB. In human and murine meningitis brain samples, HIF-1 activation was observed by immunohistochemistry. HIF-1α/VEGF expression and permeability was therefore analyzed in vitro in infected brain endothelial cells (ECs). Localization of S. pneumoniae in brain ECs from mouse/human sources was visualized in vitro and in vivo by confocal, super-resolution, and electron microscopy. S. pneumoniae infection in brain ECs resulted in upregulation of HIF-1α/VEGF by Western blotting and qRT-PCR that was associated with increased paracellular permeability, which was supported by bacterial localization at cell-cell junctions. RNA sequencing of brain microvessels from hematogenously infected mice with increased permeability and S. pneumoniae deposition in the brain showed upregulation of genes in HIF-1α/VEGF pathway. Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells and by using primary brain ECs from HIF-1α KO mice revealed a reduced endothelial permeability and transmigration of S. pneumoniae. We thus demonstrate a critical role for HIF-1α/VEGF in transmigration of S. pneumoniae across the BBB and propose targeting this pathway to prevent BBB dysfunction in infections.
2022-09-13 | GSE122952 | GEO
Project description:d9 and d12 Mks were either cultured statically or subjected to shear flow for 30 min; at d9, half the Mks were placed back in culture for 30 min (60 min time point) Megakaryocytes (Mks) are exposed to shear flow as they migrate from the bone marrow hematopoietic compartment into circulation thus releasing platelets and pro/preplatelets directly into the blood stream. Shear forces have been now established as promoting Mk maturation and platelet biogenesis. In order to understand the underlying mechanisms that modulate the response of Mks to shear forces, we carried out transcriptional analysis on immature and mature stem cell-derived Mks that were exposed to physiologically-relevant shear (2.5 dyn/cm2). In immature (d9) Mks, shear exposure upregulated genes related to growth and Mk maturation, while in mature (d12) Mks, it upregulated genes involved in apoptosis and intracellular transport. Following shear-flow exposure, 6 AP-1 transcripts (ATF4, JUNB, JUN, FOSB, FOS, and JUND) were upregulated at d9 and two AP-1 proteins (JunD and c-Fos) were upregulated both at d9 and d12. Our data show that MAPK signaling is linked to both the shear-stress response and AP-1 upregulation. JNK phosphorylation increased significantly following shear stimulation, while JNK inhibition reduced shear-induced JunD protein expression. Although p38 phosphorylation did not increase following shear flow, its inhibition reduced shear-induced JunD and c-Fos protein expression. JNK inhibition reduced fibrinogen binding of d9 and d12 platelet-like particle s (PLPs) and P-selectin expression at d12 PLPs, while p38 inhibition reduced fibrinogen binding of d12 PLPs. Here we show that mechanotransduction of shear forces in Mks results in JNK activation, AP-1 upregulation, and downstream transcriptional changes that promote maturation of immature Mks and platelet biogenesis in mature Mks. Two- and Three-condition experiment (flow vs. static culture condition, d9 vs. d12, and 30 min vs. 60 min at d9); Biological replicates: 3; Technical replicates: 1 (dye-swap)
2016-02-01 | E-GEOD-75766 | biostudies-arrayexpress
Project description:Congenital vascular malformations, affecting 0.5% of the population, frequently occur in the head and neck, complicating treatment due to their vital functions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these regions in both mouse and human embryos. In this study, we expressed Pik3caH1047R in the cardiopharyngeal mesoderm (CPM) to investigate the pathogenesis of these malformations. Mice expressing Pik3caH1047R in the CPM developed abnormal vasculature restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047R promotes Vegf-a expression in endothelial cells via Hif-driven hypoxia signaling. Human samples corroborated these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, treatment with Hif-1α and Vegf-a inhibitors significantly reduced abnormal vasculature in the mouse model. Our findings highlight the role of developmental origins and hypoxia-driven mechanisms in vascular malformations, providing a basis for developing targeted therapies for these refractory conditions.
2025-03-12 | GSE279129 | GEO
Project description:The adaptive responses to oxygen depletion orchestrated by hypoxia-inducible factors (HIFs) produce profound effects on multiple pathways. A canonical metabolic response is enhanced fermentation, but this can generate an unfavorably acidic environment under poor capillary perfusion. It is unclear how cells balance the metabolic benefits of hypoxic responses against knock-on consequences on acid-base homeostasis. We studied the interplay between hypoxia and acidosis on HIF signaling in colorectal cancer cell lines that can survive acidic conditions. Hypoxia stabilized HIF-1α, but this effect was transient in combination with acidosis. By 48 h, HIF-1α induction decreased in proportion to acidification. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (CA9, PDK1), but these did not reflect a proteome-wide downregulation. Responses to acidosis and hypoxia were enriched in lysosomal proteins, but not proteasomal components, implicating the former degradation pathway in transient HIF-1α activation under acidosis. Moreover, HIF-1α decay was not due to decreased HIF1A transcription but was blocked by lysosomal inactivation (bafilomycin-A1). Acidotic hypoxia increased the abundance of lysosomes and activated autophagy by disabling the inhibitory influence of mammalian target of rapamycin complex 1, resulting in HIF-1α degradation. By blocking HIF-driven fermentative upregulation, this mechanism protects the cellular environment from deleterious acid-overloading, an outcome that outweighs the biosynthetic benefits of raised glycolytic flux under suppressed respiration. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling, but may not reflect tumor microenvironment chemistry. Consequently, acidic hypoxic tumor regions may not necessarily overlay with sites of HIF induction
2025-06-30 | PXD062474 | Pride
Project description:The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell-sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx.
2023-03-27 | GSE228311 | GEO