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BCL9L dysfunction impairs caspase-2 expression permitting aneuploidy tolerance in colorectal cancer
journal contributionposted on 2020-10-19, 14:43 authored by Carlos López-Garcia, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.
BCL9LBIDaneuploidy tolerancecaspase-2chromosomal instabilitychromosome segregation errorscolorectal cancer evolutionintratumor heterogeneitymitotic checkpointp53AgedAged, 80 and overAneuploidyAnimalsBH3 Interacting Domain Death Agonist ProteinCaspase 2Chromosome SegregationColorectal NeoplasmsCysteine EndopeptidasesDNA-Binding ProteinsHCT116 CellsHumansMiceMiddle AgedMutationProto-Oncogene Proteins c-mdm2Transcription FactorsTumor Suppressor Protein p53Swanton FC001169CBASHPFC-ackCS-ackHTS-ackGEP-ackBRF-ackOncology & Carcinogenesis1112 Oncology and Carcinogenesis1109 Neurosciences