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MYC oncogene elicits tumorigenesis associated with embryonic, ribosomal biogenesis, and tissue-lineage dedifferentiation gene expression changes

Abstract

MYC is a transcription factor frequently overexpressed in cancer. To determine how MYC drives the neoplastic phenotype, we performed transcriptomic analysis using a panel of MYC-driven autochthonous transgenic mouse models. We found that MYC elicited gene expression changes mostly in a tissue- and lineage-specific manner across B-cell lymphoma, T-cell acute lymphoblastic lymphoma, hepatocellular carcinoma, renal cell carcinoma, and lung adenocarcinoma. However, despite these gene expression changes being mostly tissue-specific, we uncovered a convergence on a common pattern of upregulation of embryonic stem cell gene programs and downregulation of tissue-of-origin gene programs across MYC-driven cancers. These changes are representative of lineage dedifferentiation, that may be facilitated by epigenetic alterations that occur during tumorigenesis. Moreover, while several cellular processes are represented among embryonic stem cell genes, ribosome biogenesis is most specifically associated with MYC expression in human primary cancers. Altogether, MYC’s capability to drive tumorigenesis in diverse tissue types appears to be related to its ability to both drive a core signature of embryonic genes that includes ribosomal biogenesis genes as well as promote tissue and lineage specific dedifferentiation.

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Fig. 1: MYC overexpression selectively dysregulates embryonic stem cell genes and tissue-lineage genes in tumorigenesis.
Fig. 2: Pathways associated with genes differentially expressed in MYC-driven tumorigenesis reflect tissue dedifferentiation.
Fig. 3: Gene expression changes in MYC-induced tumorigenesis are associated with epigenetic changes.
Fig. 4: A tumorigenesis gene signature that is highly associated with MYC expression in primary human cancers.
Fig. 5: Examples of in situ gene expression changes upon alterations in MYC status.
Fig. 6: Proposed model for how MYC overexpression results in tissue-specific selective gene expression changes in tumorigenesis.

Code availability

For transparency of methods, all the code and procedures that can be used to reproduce the results in this paper, starting from the raw data, are available at https://github.com/Yenaled/felsher and the relevant data from all public datasets used in this study (e.g., TCGA, CCLE, dbSUPER, etc.) are also accessible via this repository.

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Acknowledgements

We thank Andrew J. Gentles and Felsher laboratory members for their advice and guidance. We thank Stanford Research Computing Center for computational resources, including the Sherlock cluster. We are grateful for the public data from TCGA and from the Broad Institute’s CCLE.

Funding

This work was funded by National Institutes of Health (NIH) grants: R35 CA253180, R01 CA089305, R01 CA170378, and U01 CA188383, with additional support as follows. DKS - UCLA-Caltech Medical Scientist Training Program (NIH NIGMS training grant T32 GM008042). AD - Lymphoma Research Foundation. RD - NIH grant CA222676 from the National Cancer Institute (NCI), American College of Gastroenterology Junior Faculty Career Development Grant. AMG - Stanford Cancer Translational Nanotechnology Training T32 Training Grant CA196585 (NCI). DFL - Tumor Biology Training Grant (NIH 5T32CA009151-38), Stanford University (NCI), Burroughs Wellcome Fund Postdoctoral Enrichment Award, Research Supplement Award (NCI), 3U01CA188383-03S1, and (K01) CA234453 (NCI).

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DKS: conceptualization, methodology, software, validation, formal analysis, investigation, resources, data curation, writing – original draft preparation, writing – review and editing, visualization, project administration. AD: formal analysis, writing – review and editing. JY: formal analysis, validation. MSK: validation. AMG: formal analysis. DIB: resources. SJA: resources. DFL: data curation, writing – review and editing. RD: formal analysis, resources, supervision, writing – review and editing. DWF: conceptualization, supervision, project administration, funding acquisition, writing – review and editing

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Correspondence to Dean W. Felsher.

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Sullivan, D.K., Deutzmann, A., Yarbrough, J. et al. MYC oncogene elicits tumorigenesis associated with embryonic, ribosomal biogenesis, and tissue-lineage dedifferentiation gene expression changes. Oncogene 41, 4960–4970 (2022). https://doi.org/10.1038/s41388-022-02458-9

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