RORγ modulates the extracellular matrix to facilitate hepatocellular carcinoma growth and metastasis
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ABSTRACT:
PROVIDER: PRJNA982719 | ENA |
REPOSITORIES: ENA
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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.
2024-01-24 | GSE234660 | GEO
Project description:Extracellular matrix interactions play essential roles in normal physiology and many pathological processes. Here, we report a novel screening platform capable of measuring phenotypic responses to combinations of ECM molecules. While the importance of ECM interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Using a genetic mouse model of lung adenocarcinoma, we measured the ECM-dependent adhesion of tumor-derived cells. Hierarchical clustering of adhesion profiles generated using this platform differentially segregated metastatic cell lines from primary tumor lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8, or laminin. These interactions appear to be mediated in part by α3β1 integrin both in vitro and in vivo. We show that these galectins also correlate with human disease at both a transcriptional and histological level. Thus, our in vitro platform allowed us to interrogate the interactions of metastatic cells with their surrounding environment, and identified ECM and integrin interactions that could lead to therapeutic targets for metastasis prevention. Cell lines derived from murine lung primary adenocarcinomas and their metastases (Winslow et al., 2011 Nature 473:101-104)
2012-10-11 | E-GEOD-40222 | biostudies-arrayexpress
Project description:We describe changes to the transcriptomes of 4t1 mammary gland carcinoma cells in different matrix environments and with and without T cells
2022-08-01 | GSE181601 | GEO
Project description:Extracellular matrix interactions play essential roles in normal physiology and many pathological processes. Here, we report a novel screening platform capable of measuring phenotypic responses to combinations of ECM molecules. While the importance of ECM interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Using a genetic mouse model of lung adenocarcinoma, we measured the ECM-dependent adhesion of tumor-derived cells. Hierarchical clustering of adhesion profiles generated using this platform differentially segregated metastatic cell lines from primary tumor lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8, or laminin. These interactions appear to be mediated in part by α3β1 integrin both in vitro and in vivo. We show that these galectins also correlate with human disease at both a transcriptional and histological level. Thus, our in vitro platform allowed us to interrogate the interactions of metastatic cells with their surrounding environment, and identified ECM and integrin interactions that could lead to therapeutic targets for metastasis prevention.
2012-10-11 | GSE40222 | GEO
Project description:Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. The treatment strategy has remained virtually unchanged over the past 40 years. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in osteosarcoma. OS exhibits a hyperactivated OXPHOS program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1β and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Knockdown or pharmacological inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression in multiple cell-based xenograft models and in chemotherapy-resistant, patient-derived xenograft (PDX) models and sensitized OS tumors to chemotherapy without obvious toxicity in mice. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provide a potential therapeutic strategy for this deadly disease.
2024-04-15 | GSE261067 | GEO
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.
2019-08-04 | GSE131856 | GEO
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.
2019-08-04 | GSE126380 | GEO
Project description:We show that RORγ functions as a master activator of the entire mevalonate pathway-cholesterol biosynthesis program in the porcine liver. RORγ genome-wide binding enrichments in the liver were significantly reduced in response to mycotoxin exposure.
2024-02-01 | GSE166520 | GEO
Project description:Natural compounds ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have been at clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target for castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) and demonstrated that tumor cell RORγ directly activates gene programs such as androgen receptor (AR) signaling and cholesterol metabolism. Previous studies also demonstrated that UA and digoxin are potential RORγt antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function in cancer cells, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA down-regulates RORγ-stimulated AR expression and AR signaling, whereas digoxin up-regulates AR signaling pathway. In TNBC cells, UA but not digoxin alters RORγ-controlled gene programs of cell proliferation, apoptosis and cholesterol-biosynthesis.Together, our study reveals for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in the cancer cells. Our finding that RORγ is a direct target of UA in cancer cells will help select patients with tumors that likely respond to UA treatment.
2023-05-17 | GSE230039 | GEO
Project description:We report here that RORγ, a nuclear receptor family member, unexpectedly mediates MDR1/ABCB1 overexpression. RORγ plays an important role in controlling the functions of subsets of immune cells and has been an attractive target for autoimmune diseases. We found that its small-molecule antagonists are efficacious in re-sensitizing DTX and CTX cross-resistant CRPC cells and tumors to taxanes in both androgen receptor (AR)-positive and -negative models. Our mechanistic analyses revealed that combined treatment with RORγ antagonists and taxane elicited a robust synergy in killing the resistant cells, which involves a coordinated alteration of p53, Myc and E2F-controlled programs critical for both intrinsic and extrinsic apoptosis, survival and cell growth. Our results suggest that targeting RORγ with small-molecule inhibitors is a novel strategy for chemotherapy resensitization in tumors with MDR1 overexpression.
2019-10-12 | GSE138751 | GEO