BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer

Carlos López-García, 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 DanielsenMarco Novelli, Ian Tomlinson, Charles Swanton

    Research output: Contribution to journalJournal articleResearchpeer-review

    358 Downloads (Pure)

    Abstract

    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.
    Original languageEnglish
    JournalCancer Cell
    Volume31
    Issue number1
    Pages (from-to)79-93
    Number of pages15
    ISSN1535-6108
    DOIs
    Publication statusPublished - 2016

    Keywords

    • aneuploidy tolerance
    • chromosomal instability
    • BCL9L
    • caspase-2
    • p53
    • intratumor heterogeneity
    • chromosome segregation errors
    • mitotic checkpoint
    • BID
    • colorectal cancer evolution

    Cite this

    López-García, C., Sansregret, L., Domingo, E., McGranahan, N., Hobor, S., Birkbak, N. J., Horswell, S., Grönroos, E., Favero, F., Rowan, A. J., Matthews, N., Begum, S., Phillimore, B., Burrell, R., Oukrif, D., Spencer-Dene, B., Kovac, M., Stamp, G., Stewart, A., ... Swanton, C. (2016). BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer. Cancer Cell, 31(1), 79-93. https://doi.org/10.1016/j.ccell.2016.11.001