Dataset Information

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

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.

SUBMITTER: Lopez-Garcia C

PROVIDER: S-EPMC5225404 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

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

López-García Carlos C Sansregret Laurent L Domingo Enric E McGranahan Nicholas N Hobor Sebastijan S Birkbak Nicolai Juul NJ Horswell Stuart S Grönroos Eva E Favero Francesco F Rowan Andrew J AJ Matthews Nicholas N Begum Sharmin S Phillimore Benjamin B Burrell Rebecca R Oukrif Dahmane D Spencer-Dene Bradley B Kovac Michal M Stamp Gordon G Stewart Aengus A Danielsen Havard H Novelli Marco M Tomlinson Ian I Swanton Charles C

Cancer cell 20170101 1

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 heterog ...[more]

PMID: 28073006

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Project description:Candida species are the most common human fungal pathogens worldwide. Although C. albicans remains the predominant cause of candidiasis, infections caused by non-albicans Candida species, including C. parapsilosis, are increasing. In C. albicans, genome plasticity has been shown to be a prevalent strategy of adaptation to stresses. However, the role of aneuploidy in C. parapsilosis is largely unknown. In this study, we found that six different aneuploid karyotypes conferred adaptation to the endoplasmic reticulum stress inducer tunicamycin (TUN) in C. parapsilosis. Interestingly, a specific aneuploidy including trisomy of chromosome 6 (Chr6x3) also enabled cross-tolerance to aureobasidin A (AbA), a sphingolipid biosynthesis inhibitor. Consistent with this, selection on AbA identified adaptors with three different aneuploid karyotypes, including Chr6x3, which also enabled cross-tolerance to both AbA and TUN. Therefore, as in other Candida species, recurrent aneuploid karyotypes enable the adaptation of C. parapsilosis to specific stresses, and specific aneuploidies enable cross-adaptation to different stresses. IMPORTANCE Candida parapsilosis is an emerging human fungal pathogen, especially prevalent in neonates. Aneuploidy, having uneven numbers of chromosomes, is a well-known mechanism for adapting to stress in Candida albicans, the most common human fungal pathogen. In this study, we exposed C. parapsilosis to two very different drugs and selected for rare cells that grew in one of the drugs. We found that the majority of isolates that grew in the drugs had acquired an extra copy of one of several aneuploid chromosomes and that specific aneuploid chromosomes appeared in several independent cell clones. Importantly, an extra copy of chromosome 6 was detected following selection in either one of the drugs, and this extra chromosome conferred the ability to grow in both drugs, a property called cross-adaptation, or cross-tolerance. Thus, this study highlights the genome plasticity of C. parapsilosis and the ability of an extra copy of a single chromosome to promote cell growth in the presence of more than one drug.

Dataset Information

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

Publications

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

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