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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_1_CAF_NF]

ABSTRACT: Analysis of gene expression profiles of three cancer-associated fibroblasts (CAFs) and four normal fibroblasts (NFs), which are derived from tumor tissues and adjacent normal mucosa of colorectal cancer patients, respectively.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93253 | GEO | 2019/01/30

REPOSITORIES: GEO

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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.

2019-01-30 | GSE93254 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-01-30 | GSE93255 | GEO

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

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

| PRJNA360422 | ENA

Hypoxia and HIF-1α Regulate Collagen Production in Keloids

Project description:Keloids are reactive or spontaneous fibroproliferative dermal tumors characterized by the exaggerated and uncontrolled accumulation of extracellular collagen. Current approaches to mitigate keloidogenesis are largely procedural in nature. However, a better understanding of its biological drivers may lead to novel targeted treatments for keloids. Through whole-genome expression analysis, we found that a HIF-1α transcriptional footprint is preferentially upregulated (activation score=2.024; p=1.05E-19) in keloid fibroblasts (KFs) compared to normal dermal fibroblasts (NFs). We verified that HIF-1α protein is more strongly expressed in keloid specimens compared to normal skin (p=0.035) and that hypoxia (1% O2) leads to increased collagen, especially in the extracellular compartment. Collagen levels were uniformly reduced by selective HIF-1α inhibitor CAY10585. Our results indicate that collagen secretion may be intimately linked to a hypoxic microenvironment within keloid tumors and that HIF-1α blockade could be a novel avenue of treatment for these tumors.

2020-02-22 | GSE145725 | GEO