Identification of Ankrd35 as a mediator of cisplatin response in non-small cell lung cancer by in vivo screening of murine tumor derived xenografts
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE136317 | GEO | 2021/11/11
REPOSITORIES: GEO
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Project description:Using pooled shRNA libraries, we performed a focused screen of 515 genes selected for involvement in response to chemotherapy. The results of this screen confirmed Notch signaling is important for primary tumor cell survival and the importance of key DNA damage response regulators for platinum-induced damage, including Ercc1. Our results establish Ankrd35, a previously uncharacterized ankyrin repeat domain protein, as an important mediator of chemoresistance in ex vivo cultures.
2021-11-11 | GSE136316 | GEO
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Project description:Increasing evidence has shown that chemoresistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long noncoding RNAs (lncRNAs) play pivotal roles in tumour metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin resistance induced EMT and metastasis are not well understood. In this study, a Chemotherapy Induced Long non-coding RNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells.Upregulation of CILA1 promotes EMT, invasiveness and chemoresistance in TSCC cells, whereas the inhibition of CILA1 expression induces MET and chemosensitivity and inhibis the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/ β-catenin signalling pathway.High CILA1 expression levels and low levesl of phosphorylated β-catenin were closely associated with cisplatin-resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for Increasing evidence has shown that chemoresistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long noncoding RNAs (lncRNAs) play pivotal roles in tumour metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin resistance induced EMT and metastasis are not well understood. In this study, a Chemotherapy Induced Long non-coding RNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells.Upregulation of CILA1 promotes EMT, invasiveness and chemoresistance in TSCC cells, whereas the inhibition of CILA1 expression induces MET and chemosensitivity and inhibis the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/ β-catenin signalling pathway.High CILA1 expression levels and low levesl of phosphorylated β-catenin were closely associated with cisplatin-resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for the chemosensitivity of TSCC tumours and a therapeutic target for TSCC treatment.
2018-05-01 | GSE111585 | GEO
Project description:Identification of Ankrd35 as a mediator of cisplatin response in non-small cell lung cancer by in vivo screening of murine tumor derived xenografts
| PRJNA562170 | ENA
Project description:Breast cancer is a heterogeneous collection of disease arising from the breast with distinct molecular and phenotypic features. Certain subsets of patients have tumors that are particularly difficult-to-treat, which include triple-negative breast cancer (TNBC), metastatic/recurrent disease and rare histological variants. To delineate the underlying biology and identify therapeutic candidates for these patients, a series of 37 breast cancer patient-derived xenografts (PDX) from both chemo-naïve and pre-treated specimens was generated from 81 transplant attempts. Whole-genome and transcriptome sequencing revealed marked fidelity of the molecular landscape for the majority of PDXs in comparison to parental tumors. Reverse-phase protein array analysis of PDXs further identified potential therapeutic targets. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases was the most common pattern of dissemination and observed in 34.5% of models. Three PDXs recapitulated the metastatic localization seen in the corresponding patients, including two lines with high-frequency metastases to multiple vital organ systems, while another PDX displayed tropism to the skull-base. Chemosensitivity profiling was performed in vivo with standard-of-care agents (doxorubicin, cisplatin, gemcitabine or paclitaxel), where multi-drug chemoresistance was found in 60.0% of PDXs and 64.7% of responses were concordant with pre-engraftment responses observed in the patient. Consolidating chemogenomic data identified potentially actionable features in 97.2% of PDXs, and marked regressions were seen in vivo when a subset of these underwent proof-of-concept functional studies. This included FGFR inhibitor sensitivity in a FGFR1-amplified lobular carcinoma, mTOR inhibitor sensitivity in a recurrent neuroendocrine breast cancer with proteomic evidence of mTOR/PI3K activation, and platinum sensitivity in a TNBC with BRCA1 germline mutation predicted as benign. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for both discovery and validation preclinical studies on difficult-to-treat breast tumors.
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2017-07-24 | GSE93793 | GEO
Project description:Epithelial ovarian cancer (EOC) represents the gynecologic cancer with the highest mortality rate. Despite a high initial response to chemotherapy, the majority of patients with advanced EOC relapses and subsequently develops chemoresistance that results in treatment failure and death of the patient. AIM: we have generated an isogenic model of PT-resistance in a panel of 3 EOC cell lines. microRNA profiling was used to identify new molecular pathway that regulate chemoresistance.
2017-07-24 | GSE93794 | GEO
Project description:Multiple DNA methylation changes have been associated with the acquisition of drug resistance; however it remains uncertain how many of these changes may represent critical DNA methylation drivers of chemoresistance. Using genome-wide DNA methylation profiling across 27,578 CpG sites on Illumina HumanMethylation27 bead array we identified loci at 4092 genes becoming hypermethylated in the chemoresistant A2780/cp70 ovarian tumour cell line compared to the parental sensitive A2780 line. Hypermethylation at CpG islands (CGI) is often associated with transcriptional silencing, however only 245 of these hypermethylated genes become down-regulated in A2780/cp70 as measured by microarray expression profiling. Treatment with the demethylating agent Decitabine induces re-sensitisation to cisplatin and resulted in re-expression of 41 of the down-regulated genes in cisplatin-resistant cells at the time point when re-sensitisation occurs. 13 of the 41 genes were consistently hypermethylated in two further independent cisplatin-resistant A2780 cell derivatives. Nine out of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS, PSMB9) acquired methylation at CpG sites in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 candidate genes acquired methylation in drug-resistant in vivo-derived ovarian cancer sustaining (side population) cells. Therefore, this small set of genes are potential key drivers of chemoresistance and should be further evaluated as predictive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in two cisplatin sensitive cell lines and three cisplatin resistant cell lines derived in vitro, four pairs of cisplatin sensitive and resistant cell lines derived in vivo, 7 pairs of tumour tissues obtained from patients before chemotherapy and at disease relapse, 2 pairs of IGROV1 SP and NSP cells. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using biological and technical replicates of matched chemosensitive/chemoresistant ovarian cancer cell lines PEO1/PEO4. Differential methylation cutoff was estimated from two biological replicates by bootstrap resampling.
2011-12-20 | E-GEOD-28647 | biostudies-arrayexpress
Project description:Background: Malignant mesothelioma is an aggressive cancer with poor prognosis. It is characterized by prominent extracellular matrix, mesenchymal tumor cell phenotypes and chemoresistance. In this study, the ability of pirfenidone to alter mesothelioma cell proliferation and migration as well as mesothelioma tumor microenvironment was evaluated. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis and has also anti-proliferative activities. Aims: Transcriptional profiling using RNA sequencing of human mesothelioma xenograft tumors treated with PBS or pirfenidone. Aim was to compare extracellular matrix and fibrosis related genes. Results: Treatment of mice harboring mesothelioma xenografts with pirfenidone alone did not reduce tumor proliferation in vivo. However, pirfenidone modified the tumor microenvironment by reducing the expression of extracellular matrix associated genes. In addition, GREM1 expression was downregulated by pirfenidone in vivo. Conclusion: By reducing two major upregulated pathways in mesothelioma and by targeting tumor cells and the microenvironment pirfenidone may present a novel anti-fibrotic and anti-cancer adjuvant therapy for mesothelioma.
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Project description:Mitochondria have attracted attention in cancer research as organelles associated with tumor development and response to therapy. We recently reported acquisition of resistance to cisplatin (DDP) associated with a metabolic rewiring in ovarian cancer patient-derived xenografts (PDXs) models. DDP-resistant PDXs models were obtained mimicking the clinical setting, treating mice bearing sensitive-DDP tumors with multiple cycles of DDP until the development of resistance. To further characterize the metabolic rewiring, the present study focused on tumor mitochondria. We analysed by transmission electron microscopy the mitochondria structure in two models of DDP-resistant and the corresponding DDP-sensitive PDXs and evaluated tumor mDNA content, the expression of genes and proteins involved in mitochondria functionality, and mitochondria fitness-related processes, such as autophagy. We observed a decrease in the number of mitochondria paralleled by an increased volume in DDP-resistant versus DDP-sensitive PDXs. DDP-resistant PDXs presented a higher percentage of damaged mitochondria, in particular of type 2 (concave-shape), and type 3 (cristolysis) damage. We found no difference in the mDNA content, and the expression of genes involved in mitochondrial biogenesis was similar between the sensitive and resistant PDXs. An upregulation of some genes involved in mitochondrial fitness in DDP-R versus DDP-S PDXs was observed. At protein level, no difference in the expression of proteins involved in mitochondrial function and biogenesis, and in autophagy/mitophagy was found. We here reported that the acquisition of DDP resistance is associated with morphological alterations in mitochondria, even if we couldn't find any dysregulation in the studied genes/proteins that could explain the observed differences.
| S-EPMC8167697 | biostudies-literature