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 Danielsen; Marco Novelli; Ian Tomlinson; Charles Swanton

doi:10.1016/j.ccell.2016.11.001

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

52 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cancer Cell
Vol/bind	31
Udgave nummer	1
Sider (fra-til)	79-93
Antal sider	15
ISSN	1535-6108
DOI	https://doi.org/10.1016/j.ccell.2016.11.001
Status	Udgivet - 9 jan. 2017
Udgivet eksternt	Ja

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10.1016/j.ccell.2016.11.001

http://www.cell.com/article/S1535610816305074/pdfLicens: CC BY

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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. (2017). 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

López-García, C, Sansregret, L, Domingo, E, McGranahan, N, Hobor, S, Birkbak, NJ, Horswell, S, Grönroos, E, Favero, F, Rowan, AJ, Matthews, N, Begum, S, Phillimore, B, Burrell, R, Oukrif, D, Spencer-Dene, B, Kovac, M, Stamp, G, Stewart, A, Danielsen, H, Novelli, M, Tomlinson, I & Swanton, C 2017, 'BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer', Cancer Cell, bind 31, nr. 1, s. 79-93. https://doi.org/10.1016/j.ccell.2016.11.001

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title = "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.",

keywords = "Aged, Aged, 80 and over, Aneuploidy, Animals, BH3 Interacting Domain Death Agonist Protein/physiology, Caspase 2/analysis, Chromosome Segregation, Colorectal Neoplasms/genetics, Cysteine Endopeptidases/analysis, DNA-Binding Proteins/genetics, HCT116 Cells, Humans, Mice, Middle Aged, Mutation, Proto-Oncogene Proteins c-mdm2/physiology, Transcription Factors/genetics, Tumor Suppressor Protein p53/physiology",

author = "Carlos L{\'o}pez-Garc{\'i}a and Laurent Sansregret and Enric Domingo and Nicholas McGranahan and Sebastijan Hobor and Birkbak, {Nicolai Juul} and Stuart Horswell and Eva Gr{\"o}nroos and Francesco Favero and Rowan, {Andrew J} and Nicholas Matthews and Sharmin Begum and Benjamin Phillimore and Rebecca Burrell and Dahmane Oukrif and Bradley Spencer-Dene and Michal Kovac and Gordon Stamp and Aengus Stewart and Havard Danielsen and Marco Novelli and Ian Tomlinson and Charles Swanton",

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T1 - BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer

AU - López-García, Carlos

AU - Sansregret, Laurent

AU - Domingo, Enric

AU - McGranahan, Nicholas

AU - Hobor, Sebastijan

AU - Birkbak, Nicolai Juul

AU - Horswell, Stuart

AU - Grönroos, Eva

AU - Favero, Francesco

AU - Rowan, Andrew J

AU - Matthews, Nicholas

AU - Begum, Sharmin

AU - Phillimore, Benjamin

AU - Burrell, Rebecca

AU - Oukrif, Dahmane

AU - Spencer-Dene, Bradley

AU - Kovac, Michal

AU - Stamp, Gordon

AU - Stewart, Aengus

AU - Danielsen, Havard

AU - Novelli, Marco

AU - Tomlinson, Ian

AU - Swanton, Charles

PY - 2017/1/9

Y1 - 2017/1/9

N2 - 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.

AB - 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.

KW - Aged

KW - Aged, 80 and over

KW - Aneuploidy

KW - Animals

KW - BH3 Interacting Domain Death Agonist Protein/physiology

KW - Caspase 2/analysis

KW - Chromosome Segregation

KW - Colorectal Neoplasms/genetics

KW - Cysteine Endopeptidases/analysis

KW - DNA-Binding Proteins/genetics

KW - HCT116 Cells

KW - Humans

KW - Mice

KW - Middle Aged

KW - Mutation

KW - Proto-Oncogene Proteins c-mdm2/physiology

KW - Transcription Factors/genetics

KW - Tumor Suppressor Protein p53/physiology

U2 - 10.1016/j.ccell.2016.11.001

DO - 10.1016/j.ccell.2016.11.001

M3 - Journal article

C2 - 28073006

SN - 1535-6108

VL - 31

SP - 79

EP - 93

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

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

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