Enhanced combination treatment on osteosarcoma by mitigating drug-induced oncogenic signaling pathway activation
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ABSTRACT:
PROVIDER: PRJNA1166301 | ENA |
REPOSITORIES: ENA
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Project description:Osteosarcoma is a prevalent primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors emerged as potential treatment for osteosarcoma due to the critical role of kinases regulating network. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a systematic combination screening of kinase inhibitors was further conducted in osteosarcoma cells. Among 190 pair-wise combinations, 44 exhibited strong synergistic antitumor efficacy. Notably, the combination of the ALK inhibitor Ceritinib and the FLT3 inhibitor Crenolanib showed significant synergistic effects against osteosarcoma cell lines, patient-derived organoids in vitro, and xenograft models in vivo. This combination also effectively mitigated the compensatory activation of oncogenic signaling pathways, a common resistance mechanism to single-agent therapies. Our findings provide compelling evidence that dual kinase inhibition targeting ALK and FLT3 can effectively exploit pharmacological vulnerabilities in osteosarcoma, suggesting a promising therapeutic strategy for clinical application. This combinatorial approach could potentially overcome the limitations of single-agent therapies and improve outcomes for patients with osteosarcoma. Further clinical evaluation is warranted to confirm these preclinical results.
2024-10-29 | GSE278302 | GEO
Project description:SaOS2 osteosarcoma cells were cultured with or without atorvastatin (10 µM) for 6, 15 or 24h (2 biological replcates). RNA were isolated and hybridized to RNG microarrays. Background Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor survival rate for patients. Methods We previously showed that the HMGCoA reductase inhibitors statins exhibit anti-tumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify cyr61/CCN1 as a new target of statins. Modulations of expression of cyr61 were performed in human and murine osteosarcoma cell lines to investigate in vitro cell viability, migratory potential and invasiveness. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients using tissue microarray. Tumor behavior and metastases occurence were analysed by IM injection of modified osteosarcoma cells to BALB/c mice. Results Transcriptome comparisons revealed that statins down-regulate cyr61 expression in SaOS2 cells. Cyr61 silencing in human and murine osteosarcoma cell lines enhanced cell death, but reduced cell migration and cell invasion compared to parental cells whereas cyr61 overexpression had opposite effects. Tissue microarray analysis demonstrated that cyr61 protein expression is higher in human osteosarcoma compared to normal bone tissue and is further increased in metastatic tissues. In vivo, cyr61 overexpression in osteosarcoma cells enhanced lung metastases development whereas cyr61 silencing strongly reduced metastases in mice. Conclusion The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma. Dye balance-experiment comparing atorvastatin versus untreated cells at 6, 15 and 24 hours using 2 biological replicates.
2011-02-22 | E-GEOD-24401 | biostudies-arrayexpress
Project description:SaOS2 osteosarcoma cells were cultured with or without atorvastatin (10 µM) for 6, 15 or 24h (2 biological replcates). RNA were isolated and hybridized to RNG microarrays. Background Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor survival rate for patients. Methods We previously showed that the HMGCoA reductase inhibitors statins exhibit anti-tumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify cyr61/CCN1 as a new target of statins. Modulations of expression of cyr61 were performed in human and murine osteosarcoma cell lines to investigate in vitro cell viability, migratory potential and invasiveness. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients using tissue microarray. Tumor behavior and metastases occurence were analysed by IM injection of modified osteosarcoma cells to BALB/c mice. Results Transcriptome comparisons revealed that statins down-regulate cyr61 expression in SaOS2 cells. Cyr61 silencing in human and murine osteosarcoma cell lines enhanced cell death, but reduced cell migration and cell invasion compared to parental cells whereas cyr61 overexpression had opposite effects. Tissue microarray analysis demonstrated that cyr61 protein expression is higher in human osteosarcoma compared to normal bone tissue and is further increased in metastatic tissues. In vivo, cyr61 overexpression in osteosarcoma cells enhanced lung metastases development whereas cyr61 silencing strongly reduced metastases in mice. Conclusion The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma.
2011-02-22 | GSE24401 | GEO
Project description:Osteosarcoma is the most common bone tumor that leads to high mortality in adolescents and children. The tRNA N7-methylguanosine methyltransferase METTL1 is located in chromosome 12q14.1, a region that is frequently amplified in osteosarcoma patients, while its functions and underlying mechanisms in regulation of osteosarcoma remain unknown. Herein we show that METTL1 and WDR4 are overexpressed in osteosarcoma and associated with poor patient prognosis. Knockdown of METTL1 or WDR4 causes decreased tRNA m7G modification level and impairs osteosarcoma progression in vitro and in vivo. Conversely, METTL1/WDR4 overexpression promotes osteosarcoma proliferation, migration and invasion capacities. tRNA methylation and mRNA translation profiling indicated that METTL1/WDR4 modified tRNAs enhance translation of mRNAs with more m7G tRNA-decoded codons, including extracellular matrix (ECM) remodeling effectors, which facilitates osteosarcoma progression and chemoresistance to doxorubicin.Our study demonstrates METTL1/WDR4 mediated tRNA m7G modification plays crucial oncogenic functions to enhance osteosarcoma progression and chemoresistance to doxorubicin via alteration of oncogenic mRNA translation, suggesting METTL1 inhibition combined with chemotherapy is a promising strategy for treatment of osteosarcoma patients.
2024-02-01 | GSE225515 | GEO
Project description:To determine whether enhanced self-renewal and tumorigenicity in UT2 cells (derived from the second human–mouse xenotransplantation of U2OS cell-formed osteosarcoma tissues) correlate with increased expression of stem/progenitor cell-associated genes, we measured global gene expression in MSC, U2OS and UT2 cells by microarray analysis. Compared to U2OS and MSC, molecules involved in regulation of self-renewal signaling pathways of cancer stem cells were also up-regulated in UT2 cells, including those in the Notch, Wnt, and TGF-beta pathways. These data suggest a genetic basis for the enhanced self-renewal and tumorigenicity of osteosarcoma-initiating cell in UT2 cells.
2012-12-30 | GSE30807 | GEO
Project description:Despite the advance in diagnosis and treatment, the prognosis of osteosarcoma patients remains unsatisfied. Therefore, it is imperative to identify novel therapeutic targets for osteosarcoma. Through RNA sequencing (RNA-seq) combined with functional screening, N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) was identified as a candidate therapeutic target in osteosarcoma. Upregulated NAT10 correlated with poor prognosis in osteosarcoma patients and NAT10 knockout drastically inhibited cell proliferation and metastasis in vitro and in vivo. NAT10 enhanced mRNA stability and translation efficiency of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induced transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis. Asn promote protein and nucleotide synthesis, facilitating osteosarcoma progression. Overexpression of ATF4, ASNS or supplementation of asparagine rescue the tumor inhibitory effect of NAT10 knockout.
2024-08-09 | GSE237541 | GEO
Project description:Despite the advance in diagnosis and treatment, the prognosis of osteosarcoma patients remains unsatisfied. Therefore, it is imperative to identify novel therapeutic targets for osteosarcoma. Through RNA sequencing (RNA-seq) combined with functional screening, N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) was identified as a candidate therapeutic target in osteosarcoma. Upregulated NAT10 correlated with poor prognosis in osteosarcoma patients and NAT10 knockout drastically inhibited cell proliferation and metastasis in vitro and in vivo. NAT10 enhanced mRNA stability and translation efficiency of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induced transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis. Asn promote protein and nucleotide synthesis, facilitating osteosarcoma progression. Overexpression of ATF4, ASNS or supplementation of asparagine rescue the tumor inhibitory effect of NAT10 knockout.
2024-08-09 | GSE237840 | GEO
Project description:A systematic analysis of super-enhancers identified MLX as a potential oncogene in osteosarcoma. Knockdown of MLX impaired tumor aggressiveness in vitro and in vivo, suggesting oncogenic properties of MLX. Mechanistically, silencing of MLX downregulates SLC7A11, a key gene encoding glutamate/cystine antiporter, to attenuate the uptake of cystine and interrupt the redox balance, leading to ferroptotic cell death. Pharmacological inhibition of SLC7A11 triggered massive ferroptosis and caused impaired tumor growth, providing a promising approach for osteosarcoma treatment.
2023-08-08 | GSE220173 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1, that might act as driver oncogenes through aberrant hyperactivation of mTORC1. Here, we show that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of Rheb, Tuberous Sclerosis Complex. We show that two activated mutants, Rheb-T23M and E40K, strongly drive increased cell growth and proliferation and anchorage-independent growth resulting in enhanced tumour growth in vivo. Proteomic analysis of cells expressing the mutations revealed, surprisingly, that these two mutants promote distinct oncogenic pathways with Rheb-T23M driving metabolic reprogramming and an increased reliance of glycolysis, while Rheb-E40K interacts with AMPK to regulate eukaryotic elongation factor 2 (eEF2) and autophagy. Our findings suggest that unique ‘bespoke’ combination therapies may be utilised to treat cancers according to which Rheb mutant they harbour.
2021-04-22 | PXD017006 | Pride
Project description:In order to identify the targets of miR-193a-5p in osteosarcoma U2OS cell line, we used a lentivirus-mediated expression system to overexpressing miR-193a precusor, miR-193a-5p target sequence and non-target sequence, respectively, in osteosarcoma cell line U2OS. A tandem mass tag (TMT)-based quantitative proteomic strategy was employed to identify the global profile of miR-193a-5p-regulated proteins. order to identify the targets of miR-193a-5p, we used a lentivirus-mediated expression system to overexpressing miR-193a precusor, miR-193a-5p target sequence and non-target sequence, respectively, in osteosarcoma cell line U2OS. A tandem mass tag (TMT)-based quantitative proteomic strategy was employed to identify the global profile of miR-193a-5p-regulated proteins.
2021-09-08 | PXD013987 | Pride