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Cell reports
11 22, 2022;41 (8): 111704.

MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors.

Laura Urbanski, Mattia Brugiolo, SungHee Park, Brittany L Angarola, Nathan K Leclair, Marina Yurieva, Phil Palmer, Sangram Keshari Sahu, Olga Anczuków
Author Information
  1. Laura Urbanski: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Graduate Program in Genetics and Development, UConn Health, Farmington, CT, USA.
  2. Mattia Brugiolo: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  3. SungHee Park: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  4. Brittany L Angarola: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  5. Nathan K Leclair: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Graduate Program in Genetics and Development, UConn Health, Farmington, CT, USA.
  6. Marina Yurieva: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  7. Phil Palmer: Lifebit, London, UK.
  8. Sangram Keshari Sahu: Lifebit, London, UK.
  9. Olga Anczuków: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA. Electronic address: olga.anczukow@jax.org.
PMID: 36417849 DOI: 10.1016/j.celrep.2022.111704

Abstract

MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain underexplored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the pan-cancer SF-module induces MYC-regulated splicing events and increases organoid size and invasiveness, while knockdown decreases organoid size. Finally, we uncover a MYC-activity pan-cancer splicing signature correlating with survival across tumor types. Our findings provide insight into the mechanisms of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors.

Keywords

CP: Cancer MYC RNA splicing SR proteins alternative splicing breast cancer cancer co-expression analysis co-expression modules oncogenes organoids pan-cancer splicing factors

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Grants

  1. T32 AG062409/NIA NIH HHS
  2. P30 CA034196/NCI NIH HHS
  3. R00 CA178206/NCI NIH HHS
  4. R01 CA248317/NCI NIH HHS
  5. R01 GM138541/NIGMS NIH HHS

MeSH Term

Female
Humans
Breast Neoplasms
Carcinogenesis
Oncogenes
Proto-Oncogene Proteins c-myc
RNA Splicing
RNA Splicing Factors

Chemicals

Proto-Oncogene Proteins c-myc
RNA Splicing Factors
Journal Article Research Support, N.I.H., Extramural
Article has an altmetric score of 13

Word Cloud

Created with Highcharts 10.0.0splicingMYCpan-cancercanceralternativefactorsbreastregulatesnetworkco-expressedtumorsSF-modulecorrelatingacrosstumortypeseventsorganoidsMYC-regulatedorganoidsizeco-expressiondysregulated>50%cancersdirecttargetingclinicallyunsuccessfulTargetingdownstreameffectorpathwaysrepresentsattractivemRNAmechanisticlinksmachineryremainunderexploredidentifySF-modulesMYC-activeoneactivity33mammarycellmodelsactivationleadsco-upregulationmoduleSFschanges>4000co-overexpressioninducesincreasesinvasivenessknockdowndecreasesFinallyuncoverMYC-activitysignaturesurvivalfindingsprovideinsightmechanismsdevelopmenttherapeuticsMYC-drivenoncogenicCP:CancerRNASRproteinsanalysismodulesoncogenes

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