Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts.

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MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.", "claims": [{"id": "claim-method", "statement": "Due to small and uneven sample group sizes, differences in protein abundance, phosphosite abundance, and kinase activity between subgroups were calculated using one-way ANOVA (aov function in the R stats package coupled with the ANOVA function within car 3.0–8)11 with Tukey post-hoc and Benjamini–Hochberg correction for multiple hypothesis testing (TukeyHSD function from the stats package). The significance of differences in actinomycin D IC50 values between cell lines was determined by Student’s t-test using the t.test function in R.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35977718", "locator": "sections[3] \"Experimental Design and Statistical Rationale\" paragraph 2", "quote": "Due to small and uneven sample group sizes, differences in protein abundance, phosphosite abundance, and kinase activity between subgroups were calculated using one-way ANOVA (aov function in the R stats package coupled with the ANOVA function within car 3.0–8)11 with Tukey post-hoc and Benjamini–Hochberg correction for multiple hypothesis testing (TukeyHSD function from the stats package)."}, {"asset": "source:pmid:35977718", "locator": "sections[3] \"Experimental Design and Statistical Rationale\" paragraph 2", "quote": "The significance of differences in actinomycin D IC50 values between cell lines was determined by Student’s t-test using the t.test function in R."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE18 partner repository with the dataset identifier PXD035070.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35977718", "locator": "sections[10] \"Data Acquisition and Protein Identification\" paragraph 3", "quote": "Mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE18 partner repository with the dataset identifier PXD035070."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors, and actinomycin D sensitivity is significantly associated with increased abundance of MYC and MYC target genes.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:35977718", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models."}, {"asset": "source:pmid:35977718", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors, and actinomycin D sensitivity is significantly associated with increased abundance of MYC and MYC target genes.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:35977718"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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