RORγ modulates the extracellular matrix to facilitate hepatocellular carcinoma growth and metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA982719 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24894440.fastq.gz | Fastqsanger.gz | |||
| SRR24894441.fastq.gz | Fastqsanger.gz |
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Project description:Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), predicting an essential role of abnormal matrix in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. The elevated RORγ increased Fibronectin-1 deposition, cell-matrix adhesion, collagen production and cross-linkling, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis via ECM remodeling in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, the elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player in HCC progression by remodeling ECM and as an attractive therapeutic target for advanced HCC.
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Project description:Peritoneal metastasis (PM) is diagnosed in almost half of patients with advanced gastric cancer (GCa) and has a very poor prognosis. However, the molecular mechanisms of PM in GCa remain poorly understood. Here, we show that the elevated expression of RAR-related orphan receptor gamma (RORγ) in GCa tumors is a key driver of PM. RORγ drives GCa progression and metastasis by assembling a transcriptional complex with HIF-1α that regulates the expression of HIF-1α targets via recruitment of RNA polymerase II and p300. Mechanistically, RORγ hijacks HIF-1α to disrupt the interaction between HIF-1α and PHD3, leading to decreased HIF-1α hydroxylation, ubiquitylation and increased HIF-1α accumulation, nuclear translocation, and transactivation. RORγ antagonists block tumor growth and PM in multiple xenograft GCa models, and they effectively sensitize GCa tumors to chemotherapy in mice. Thus, our study uncovers a mechanism of RORγ-driven PM and offers a potential therapeutic option against advanced GCa.
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Project description:Peritoneal metastasis (PM) is diagnosed in almost half of patients with advanced gastric cancer (GCa) and has a very poor prognosis. However, the molecular mechanisms of PM in GCa remain poorly understood. Here, we show that the elevated expression of RAR-related orphan receptor gamma (RORγ) in GCa tumors is a key driver of PM. RORγ drives GCa progression and metastasis by assembling a transcriptional complex with HIF-1α that regulates the expression of HIF-1α targets via recruitment of RNA polymerase II and p300. Mechanistically, RORγ hijacks HIF-1α to disrupt the interaction between HIF-1α and PHD3, leading to decreased HIF-1α hydroxylation, ubiquitylation and increased HIF-1α accumulation, nuclear translocation, and transactivation. RORγ antagonists block tumor growth and PM in multiple xenograft GCa models, and they effectively sensitize GCa tumors to chemotherapy in mice. Thus, our study uncovers a mechanism of RORγ-driven PM and offers a potential therapeutic option against advanced GCa.
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Project description:Expression profile of hepatocellular carcinoma-matrix interaction
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Project description:Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.
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Project description:We show that triple-negative breast cancer (TNBC) exhibits a hyper-activated MVA-CB program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol contents and synthesis rate while preserving host cholesterol homeostasis. We demonstrate, for the first time, that RORγ functions as a master activator of the entire MVA-CB program, dominantly over SREBP2, through its own direct binding and facilitating the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces MVA-CB chromatin acetylation. RORγ antagonists cause sustained TNBC tumor regression in patient-derived and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our studies uncover a previously unsuspected master regulator of MVA-CB and an attractive target for TNBC.
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Project description:We show that triple-negative breast cancer (TNBC) exhibits a hyper-activated MVA-CB program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol contents and synthesis rate while preserving host cholesterol homeostasis. We demonstrate, for the first time, that RORγ functions as a master activator of the entire MVA-CB program, dominantly over SREBP2, through its own direct binding and facilitating the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces MVA-CB chromatin acetylation. RORγ antagonists cause sustained TNBC tumor regression in patient-derived and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our studies uncover a previously unsuspected master regulator of MVA-CB and an attractive target for TNBC.
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