Transcriptome profiling of caspase-2 deficient EµMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling

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dc.contributor.authorDorstyn, L.
dc.contributor.authorHackett-Jones, E.
dc.contributor.authorNikolic, A.
dc.contributor.authorNorris, M.D.
dc.contributor.authorLim, Y.
dc.contributor.authorToubia, J.
dc.contributor.authorHaber, M.
dc.contributor.authorKumar, S.
dc.date.issued2019
dc.description.abstractCaspase-2 is a highly conserved cysteine protease with roles in apoptosis and tumor suppression. Our recent findings have also demonstrated that the tumor suppression function of caspase-2 is context specific. In particular, while caspase-2 deficiency augments lymphoma development in the EμMyc mouse model, it leads to delayed neuroblastoma development in Th-MYCN mice. However, it is unclear how caspase-2 mediates these differential outcomes. Here we utilized RNA sequencing to define the transcriptomic changes caused by caspase-2 (Casp2-/-) deficiency in tumors from EμMyc and Th-MYCN mice. We describe key changes in both lymphoma and neuroblastoma-associated genes and identified differential expression of the EGF-like domain-containing gene, Megf6, in the two tumor types that may contribute to tumor outcome following loss of Casp2. We identified a panel of genes with altered expression in Th-MYCN/Casp2-/- tumors that are strongly associated with neuroblastoma outcome, with roles in melanogenesis, Wnt and Hippo pathway signaling, that also contribute to neuronal differentiation. In contrast, we found that key changes in gene expression in the EμMyc/Casp2-/- tumors, are associated with increased immune signaling and T-cell infiltration previously associated with more aggressive lymphoma progression. In addition, Rap1 signaling pathway was uniquely enriched in Casp2 deficient EμMyc tumors. Our findings suggest that Casp2 deficiency augments immune signaling pathways that may be in turn, enhance lymphomagenesis. Overall, our study has identified new genes and pathways that contribute to the caspase-2 tumor suppressor function and highlight distinct roles for caspase-2 in different tissues.
dc.description.statementofresponsibilityLoretta Dorstyn, Emily Hackett-Jones, Andrej Nikolic, Murray D. Norris, Yoon Lim, John Toubia, Michelle Haber, and Sharad Kumar
dc.identifier.citationCell Death and Disease, 2019; 10(2):56-1-56-16
dc.identifier.doi10.1038/s41419-018-1296-0
dc.identifier.issn2041-4889
dc.identifier.issn2041-4889
dc.identifier.orcidKumar, S. [0000-0001-7126-9814]
dc.identifier.urihttp://hdl.handle.net/2440/118254
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1021456
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1043057
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1103006
dc.rights© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41419-018-1296-0
dc.subjectNeurons
dc.subjectB-Lymphocytes
dc.subjectAnimals
dc.subjectMice
dc.subjectLymphoma
dc.subjectNeuroblastoma
dc.subjectThoracic Neoplasms
dc.subjectDisease Models, Animal
dc.subjectSurvival Analysis
dc.subjectGene Expression Profiling
dc.subjectSignal Transduction
dc.subjectCell Differentiation
dc.subjectTumor Suppressor Protein p53
dc.subjectCaspase 2
dc.subjectN-Myc Proto-Oncogene Protein
dc.titleTranscriptome profiling of caspase-2 deficient EµMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling
dc.title.alternativeTranscriptome profiling of caspase-2 deficient EmuMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling
dc.typeJournal article
pubs.publication-statusPublished

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