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Intrinsic epigenetic state of primary osteosarcoma drives metastasis [ATAC-seq]

ABSTRACT: Osteosarcoma (OS) is a primary malignant bone tumor commonly affecting children, adolescents, and young adults with a potential to metastasize to distal sites, most commonly lung. Here, we mapped the active chromatin landscapes of OS patients with varying extent of disease. We integrated histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) of OS tumors from four different diseased states to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary tumors that undergo metastasis (primary mets) have a distinct enhancer landscape compared to primary tumors that remain localized (localized) during the course of disease. The difference in chromatin activity shapes the transcriptional profile of OS patients. Some of the genes like PPP1R1B, PREX1 and IGF2BP1 whose role in OS pathogenesis and metastasis remains poorly understood, exhibit increased enhancer activity in primary mets along with higher RNA levels. Genome-wide loss-of-function screens also reveal these genes to be as selective dependencies in bone sarcomas, making them promising candidates for further investigation. Overall, differential chromatin activity in primary mets occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and migration process suggestive of their role in facilitating OS metastasis. Thus, this data demonstrates that metastatic potential is intrinsically present in primary mets OS much before the occurrence of metastasis and when the cells are presented with favorable conditions to migrate and colonize at a distant site, they under undergo metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234996 | GEO | 2023/12/09

REPOSITORIES: GEO

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Project description:Osteosarcoma (OS) and Ewing’s sarcoma (EW) are the two most common pediatric solid tumors, after brain tumors. Multimodal treatments have significantly improved prognosis in localized disease but outcome is still poor in metastatic patients, for whom therapeutic options are often inadequate. Preclinical drug testing to identify promising treatment options that match the molecular make-up of these tumors is hampered by the lack of appropriate and molecularly well-characterized patient-derived models. To address this need, a panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected OS and EW tumors in NSG mice. Tumors were re-transplanted to next mice generations and fragments were collected for histopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least three passages. To evaluate the similarity of the model with primary tumor, we performed a global gene expression profiling and tissue microarrays (TMA), to assess tumor specific biomarkers on tissues from OS/EW tumors and their PDXs (1st and 3rd passage). Moreover, we verified the feasibility of these models for preclinical drug testing. We implanted 61 OS and 29 EW samples: 14/38 (37%) primary OS and 9/23 (39%) OS lung metastases successfully engrafted; while among EW, 5/26 (19%) primary samples and 1/3 (33%) metastases were established. Comparison between patient samples and PDXs, highlighted that histology and genetic characteristics of PDXs were stable and maintained over passages. In particular, correlative analysis between OS and EW samples and their PDXs was extremely high (Pearson’s r range r=0.94-0.96), while patient-derived primary cultures displayed reduced correlation with human samples (r=0.90-0.93), indicating that in vitro adaptation superimpose molecular alterations that create genetic diversion from original tumors. No significant differentially expressed gene profile was observed from the comparison between EW samples and PDXs (fold change > 2, adjusted p <0.05 at paired t-test). In OS, the comparison between OS patient-derived tumors and PDX indicated differences in 397 genes, mostly belonging to immune system functional category. This is in line with the idea that human immune cells are gradually replaced by murine counterparts upon engraftment in the mouse. As proof-of concept, two EW PDX and one OS PDX have been treated with conventional and innovated drugs to test their value in terms of drug-sensitivity prediction. Overall, our study indicated that PDX models maintained the histological and genetic markers of the tumor samples and represent reliable models to test sensitivity to novel drug associations.

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Intrinsic epigenetic state of primary osteosarcoma drives metastasis [ATAC-seq]

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