RESUMO
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these "aneuploidy addictions" could be targeted as a therapeutic strategy.
Assuntos
Proteínas de Ciclo Celular , Edição de Genes , Neoplasias , Oncogenes , Trissomia , Proteína Supressora de Tumor p53 , Humanos , Proteínas de Ciclo Celular/genética , Mutação , Neoplasias/genética , Neoplasias/terapia , Proteínas Proto-Oncogênicas/metabolismo , Edição de Genes/métodos , Proteína Supressora de Tumor p53/genética , Carcinogênese/genéticaRESUMO
Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we conducted an analysis of hundreds of human cancer cell lines and tumors with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins show dosage compensation and fail to change by the degree expected based on chromosome copy number alone. We uncovered a variety of gene groups that were recurrently buffered upon both chromosome gain and loss, including protein complex subunits and cell cycle genes. Several genetic and biophysical factors were predictive of protein buffering, highlighting complex post-translational regulatory mechanisms that maintain appropriate gene product dosage. Finally, we established that chromosomal aneuploidy has a moderate effect on the expression of oncogenes and tumor suppressors, showing that these key cancer drivers can be subject to dosage compensation as well. In total, our comprehensive analysis of aneuploidy and dosage compensation across cancers will help identify the key driver genes encoded on altered chromosomes and will shed light on the overall consequences of aneuploidy during tumor development.
Assuntos
Aneuploidia , Neoplasias , Cromossomos , Mecanismo Genético de Compensação de Dose , Dosagem de Genes , Humanos , Neoplasias/genéticaRESUMO
Aneuploidy has been recognized as a hallmark of tumorigenesis for more than 100 years, but the connection between chromosomal errors and malignant growth has remained obscure. New evidence emerging from both basic and clinical research has illuminated a complicated relationship: despite its frequency in human tumours, aneuploidy is not a universal driver of cancer development and instead can exert substantial tumour-suppressive effects. The specific consequences of aneuploidy are highly context dependent and are influenced by a cell's genetic and environmental milieu. In this Review, we discuss the diverse facets of cancer biology that are shaped by aneuploidy, including metastasis, drug resistance and immune recognition, and we highlight aneuploidy's distinct roles as both a tumour promoter and an anticancer vulnerability.
Assuntos
Aneuploidia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Evasão Tumoral/imunologia , Animais , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Camundongos , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Fenótipo , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Chromosomal instability (CIN) is a hallmark of cancer, leading to aneuploid cells. To study the role that CIN plays in tumor evolution, several mouse models have been engineered over the last 2 decades. These models have unequivocally shown that systemic high-grade CIN is embryonic lethal. We and others have previously shown that embryonic lethality can be circumvented by provoking CIN in a tissue-specific fashion. In this study, we provoke systemic high-grade CIN in adult mice as an alternative to circumvent embryonic lethality. For this, we disrupt the spindle assembly checkpoint (SAC) by alleviating Mad2 or truncating Mps1, both essential genes for SAC functioning, with or without p53 inactivation. We find that disruption of the SAC leads to rapid villous atrophy, atypia and apoptosis of the epithelia of the jejunum and ileum, substantial weight loss, and death within 2-3 weeks after the start of the CIN insult. Despite this severe intestinal phenotype, most other tissues are unaffected, except for minor abnormalities in spleen, presumably due to the lower proliferation rate in these tissues. We conclude that high-grade CIN in vivo in adult mice is most toxic to the high cell turnover intestinal epithelia.
Assuntos
Intestinos/patologia , Proteínas Mad2/fisiologia , Animais , Atrofia , Pontos de Checagem da Fase M do Ciclo Celular , Proteínas Mad2/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.
Assuntos
Compostos de Anilina/farmacologia , Benzimidazóis/farmacologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Microtúbulos/metabolismo , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Fuso Acromático/metabolismo , Quinases da Família src/antagonistas & inibidores , Aneuploidia , Instabilidade Cromossômica/efeitos dos fármacos , Sinergismo Farmacológico , Técnicas de Silenciamento de Genes , Células HT29 , Humanos , Cinética , Células MCF-7 , Microtúbulos/efeitos dos fármacos , Neoplasias/genética , Fenótipo , Polimerização/efeitos dos fármacos , Fuso Acromático/efeitos dos fármacos , Quinases da Família src/genéticaRESUMO
Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg.
Assuntos
Envelhecimento/genética , Aneuploidia , Instabilidade Cromossômica , Animais , Linhagem Celular Tumoral , Segregação de Cromossomos/genética , Modelos Animais de Doenças , Humanos , Cariótipo , Mitose/genética , Neoplasias/genéticaRESUMO
Stem cells hold enormous promise for regenerative medicine as well as for engineering of model systems to study diseases and develop new drugs. The discovery of protocols that allow for generating induced pluripotent stem cells (IPSCs) from somatic cells has brought this promise steps closer to reality. However, as somatic cells might have accumulated various chromosomal abnormalities, including aneuploidies throughout their lives, the resulting IPSCs might no longer carry the perfect blueprint for the tissue to be generated, or worse, become at risk of adopting a malignant fate. In this review, we discuss the contribution of aneuploidy to healthy tissues and how aneuploidy can lead to disease. Furthermore, we review the differences between how somatic cells and stem cells respond to aneuploidy.