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

Abstract

SummaryChromosomal 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.

Role of chromosomal instability in cancer progression

“…Induction of aneuploidy in diploid systems leads to multiple cellular changes that result in cell death or cell cycle arrest, reviewed in (Santaguida & Amon 2015). Chromosomally unstable cells have overcome these arrest points by multiple mechanisms, some of which are beginning to be elucidated , Lopez-Garcia et al 2017. Moreover, tumours appear to have evolved a beneficial and tolerable level of CIN.…”

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

“…Aneuploid mammalian and yeast cells exhibit metabolic alterations (Williams et al, 2008), proliferation defects (Santaguida et al, 2015; Stingele et al, 2012; Tang et al, 2011; Thompson and Compton, 2010; Torres et al, 2007; Williams et al, 2008), genome instability (Blank et al, 2015; Meena et al, 2015; Ohashi et al, 2015; Passerini et al, 2016; Sheltzer et al, 2011; Zhu et al, 2012), proteotoxic stress (Oromendia et al, 2012; Santaguida et al, 2015; Santaguida and Amon, 2015b; Stingele et al, 2012; Tang and Amon, 2013), and aneuploid mammalian cells have been reported to activate p53 (Hinchcliffe et al, 2016; Li et al, 2010; López-García et al, 2017; Sansregret et al, 2017; Thompson and Compton, 2010). In addition to traits observed in a broad range of aneuploidies, aneuploid cells exhibit gene-specific phenotypes where changes in dosage of a particular gene cause a specific phenotype (i.e.…”

Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

“…13 Three recent studies shed light on the mechanism of, and the signal responsible for, CASP2 activation during mitotic catastrophe unveiling the existence of a tight connection between CASP2 and the p53 pathway. [14][15][16] By analyzing colorectal cancers and cell lines displaying high levels of CIN, either at the baseline or upon the pharmacological abrogation of the SAC or increase of replication stress, Lopez-Garcia and colleagues identified a novel mechanism of tolerance to non-diploidy based on the downregulation of CASP2 expression.…”

“…Finally, BCL9L haploinsufficiency was reported to increase the tolerance to aneuploidy by downregulating CASP2 via the inhibition of the transcription factor 4 (TCF4). 14 Fava and colleagues analyzed the cellular response to ploidy changes uncovering a similar surveillance mechanism relying on CASP2 and executed by p53. 15 Fava et al found that cells undergoing whole-genome duplication via cytokinesis failure were arrested in their proliferation by a process that involved the p53-independent activation of CASP2 by the PIDDosome.…”