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Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and overcomes chemoresistance in ovarian clear cell carcinoma

ABSTRACT: Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and overcomes chemoresistance in ovarian clear cell carcinoma

PROVIDER: PRJNA930662 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23317050_1.fastq.gz	Fastqsanger.gz
	SRR23317050_2.fastq.gz	Fastqsanger.gz
	SRR23317051_1.fastq.gz	Fastqsanger.gz
	SRR23317051_2.fastq.gz	Fastqsanger.gz
	SRR23317052_1.fastq.gz	Fastqsanger.gz

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Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and overcomes chemoresistance in ovarian clear cell carcinoma

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Cancer-associated fibroblasts metabolic targeting overcomes T-cell exclusion and chemoresistance

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Metronomic doxorubicin blocks HIF-1α-mediated responses in sarcomas and augments the effects of anti-VEGF-A therapy

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.

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Cancer-associated fibroblasts metabolic targeting overcomes T-cell exclusion and chemoresistance [Human]

Project description:Cancer-associated fibroblasts metabolic targeting overcomes T-cell exclusion and chemoresistance [Human]

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Cancer-associated fibroblasts metabolic targeting overcomes T-cell exclusion and chemoresistance [Mouse]

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Targeting STAT3-Mediated Lipid Metabolism Reprogramming Overcomes Chemoresistance in Acute Myeloid Leukemia

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Hypoxic microenvironment activates GLI2 through synergistic action of TGF-β2 and HIF-1α to confer chemoresistance and poor clinical outcome in colorectal cancer [IlluminaExpr_2_CAF_SF_SD208]

Project description:Microenvironment has been suggested as an important factor contributing to how the colorectal cancer cells escape therapy, but the exact mechanism leading to chemoresistance remains elusive. Here, through modeling in vitro by cocultivation of patient-derived cancer associated fibroblasts (CAFs) with cancer stem cells (CSCs), we show that CAFs-secreted TGF-β2 is a key stromal factor that coordinates with hypoxia to promote CSC stemness and resistance to chemotherapy. GLI2, a key transcription factor of Hedgehog pathway, was identified as both necessary and sufficient in this process in which TGF-β and hypoxia-inducible factor (HIF-1α) synergize to directly induce GLI2 expression. Conversely, CSC-secreted TGF-β is also important to support the growth of CAFs but instead induce death of normal fibroblasts, suggesting a reciprocal mechanism to selectively support the CAF-CSC interaction. Small molecule inhibition of both TGF-β and GLI2 effectively reversed the chemoresistance. Finally, expression of TGFB2/HIF1A/GLI2 gene signature as a functional readout of this resistance pathway defines worse clinical outcomes and predicts patients relapse. Our observations uncover a key role of TGF-β/HIF-1α/GLI2 in microenvironment-mediated chemoresistance and reveal novel biomarker and targeting strategies to identify and treat the high risk CRC patients.

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2025-05-07 | PXD053068 | Pride

Targeting STAT3-Mediated Lipid Metabolism Reprogramming Overcomes Chemoresistance in Acute Myeloid Leukemia

Project description:Chemotherapy resistance and intolerance pose significant challenges in the effective treatment of leukemia. Among the distinctive features associated with chemoresistance, metabolic reprogramming emerges as a key factor. In this study, we unveil a novel mechanism contributing to chemoresistance in leukemia, specifically highlighting the pivotal role of altered lipid homeostasis.We found that multiple lipid metabolism processes are aberrantly activated in Ara-C resistant AML cells, with upregulation of JAK-STAT3 signaling pathways and multiple enzymes in the process of fatty acid metabolism. A potent, and highly selective STAT3 inhibitor, W1307, was designed, and exhibited significant anti-tumor activities in vitro and in vivo. Genetic and pharmacological inhibition of STAT3 leads to inhibition of lipid synthesis and catabolism, resulting lipids metabolic disorder. Mechanistically, STAT3 binds to consensus DNA response elements in the promoters of the lipid metabolism associated genes (SREBP1, CPT2) and regulates their expression. Furthermore, inhibition of STAT3 enhances the anti-tumor effect of Ara-C and sensitizes resistant AML cell line to Ara-C through disrupting lipid homeostasis and triggering lipotoxicity. Collectively, our work illuminates the pivotal role of lipid metabolism adaptation driven by STAT3 in chemoresistance. The identification of W1307 as a promising candidate compound underscores its potential as a therapeutic intervention in leukemia treatment and overcoming chemoresistance.

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