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IlAglIoxx

ABSTRACT: Inachis io (European peacock)

PROVIDER: PRJEB42130 | ENA |

REPOSITORIES: ENA

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Dataset's files

Source:

			Action	DRS
		Other
	CAJHUF01.dat.gz	Other
	CAJHUF01.fasta.gz	Fasta.gz
	CAJHUF01.master.dat	Other
	CAJHUM01.dat.gz	Other

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ilAglIoxx1

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Co-activation of Sonic hedgehog and Wnt signaling in murine retinal precursor cells drives ocular lesions with features of intraocular medulloepithelioma

Project description:Intraocular medulloepithelioma (IO-MEPL) is a rare embryonal ocular neoplasm, prevalently occurring in children. IO-MEPL share histomorphological features with CNS embryonal tumors with multilayered rosettes (ETMR), referred to as intracranial medulloepitheliomas. While Sonic hedgehog (SHH) and WNT signaling pathways are crucial for ETMR pathogenesis, the impact of these pathways on human IO-MEPL development is unclear. Gene expression analyses of human embryonal tumor samples revealed similar gene expression patterns and significant overrepresentation of SHH and WNT target genes in both IO-MEPL and ETMR. In order to unravel the function of Shh and Wnt signaling for IO-MEPL pathogenesis in vivo, both pathways were activated in retinal precursor cells in a time point specific manner. Shh and Wnt co-activation in early Sox2- or Rax- expressing precursor cells resulted in infiltrative ocular lesions that displayed extraretinal expansion. Histomorphological, immunohistochemical and molecular features showed a strong concordance with human IO-MEPL. We demonstrate a relevant role of WNT and SHH signaling in IO-MEPL and report the first mouse model to generate tumor-like lesions with features of IO-MEPL. The presented data may be fundamental for comprehending IO-MEPL initiation and developing targeted therapeutic approaches.

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RNAseq analysis of tumours from GEMMS animals to determine the effect of different aPDL1 combinations on lung tumours in situ

Project description:This study aims to identify combination treatments capable of inducing improved IO responses in lung tumours and thus, help guide decisions on the next combination arms for the HUDSON trial (post-IO). For that purpose, a lung tumour GEMM model was treated with either vehicle, PD-L1, ATR, ATR/PD-L1; Cisplatin/PD-L1/Ctla4 or VEGFR/PD-L1 and tumours collected for transcriptional profiling.

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Rational selection of syngeneic preclinical tumor models for immunotherapeutic drug discovery [aCGH]

Project description:Murine syngeneic tumor models are the cornerstone of novel immuno-oncology (IO)-based therapy development but the molecular and immunological features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Within a panel of commonly-used murine syngeneic tumor models, we showed variable responsiveness to IO-therapies. We employed aCGH, whole-exome sequencing, exon microarray analysis and flow cytometry to extensively characterise these models and revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. We further investigated this using flow cytometry, which showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor ‘inflamed’ and ‘non-inflamed’ tumor immune infiltrate phenotypes. Moreover, we found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of IO-therapy in the clinic and these differences could underlie the varying response profiles to IO-therapy between the syngeneic models. This characterisation highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of IO-therapies as well as combinations with targeted therapies in vivo.

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Project description:CD137-CIS IO

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