Proteogenomic analysis reveals adaptive strategies for alleviating the consequences of aneuploidy in cancer
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PROVIDER: PRJNA1072666 | ENA |
REPOSITORIES: ENA
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Project description:Aneuploidy is prevalent in cancer, conferring fitness advantage, multidrug resistance, and poor prognosis. In contrast, experimentally induced aneuploidy often results in adverse effects and impaired proliferation. This paradox underscores the necessity of cancer cells to adapt to abnormal chromosome numbers. To identify molecular mechanisms of adaptation to aneuploidy, we initiated in vitro evolution of cells with extra chromosomes added via microcell-mediated chromosome transfer. To this end, we cultured cells in a nutrient-rich medium for 50 passages or plated the cells at a low density and selectively collected the largest colonies originating from a single cell (colony selection). The anaylsis of somatic copy number variations in the evolved cell lines was then carried out based on low-coverage whole genome sequencing (WGS) and array-based comparative genomic hybridization (aCGH).
2024-03-04 | GSE254936 | GEO
Project description:Aneuploidy is prevalent in cancer and associates with fitness advantage and poor patient prognosis. Yet, experimentally induced aneuploidy initially leads to adverse effects and impaired proliferation, suggesting that cancer cells must adapt to aneuploidy. We performed in vitro evolution of cells with extra chromosomes and obtained cell lines with improved proliferation and gene expression changes congruent with changes in aneuploid cancers. Integrated analysis of cancer multi-omics data and model cells revealed increased expression of DNA replicative and repair factors, reduced genomic instability, and reduced lysosomal degradation. We identified E2F4 and FOXM1 as transcription factors strongly associated with adaptation to aneuploidy in vitro and in cancers and validated this finding. The adaptation to aneuploidy also coincided with specific copy number aberrations that correlate with poor patient prognosis. Chromosomal engineering mimicking these aberrations improved aneuploid cell proliferation, while loss of previously present extra chromosome impaired it. The identified common adaptation strategies suggest replication stress, genomic instability, and lysosomal stress as common liabilities of aneuploid cancers.
| S-SCDT-10_1038-S44318-025-00372-W | biostudies-other
Project description:Aneuploidy is prevalent in cancer and associates with fitness advantage and poor patient prognosis. Yet, experimentally induced aneuploidy initially leads to adverse effects and impaired proliferation, suggesting that cancer cells must adapt to aneuploidy. We performed in vitro evolution of cells with extra chromosomes and obtained cell lines with improved proliferation and gene expression changes congruent with changes in aneuploid cancers. Integrated analysis of cancer multi-omics data and model cells revealed increased expression of DNA replicative and repair factors, reduced genomic instability, and reduced lysosomal degradation. We identified E2F4 and FOXM1 as transcription factors strongly associated with adaptation to aneuploidy in vitro and in cancers and validated this finding. The adaptation to aneuploidy also coincided with specific copy number aberrations that correlate with poor patient prognosis. Chromosomal engineering mimicking these aberrations improved aneuploid cell proliferation, while loss of previously present extra chromosomes impaired it. The identified common adaptation strategies suggest replication stress, genomic instability, and lysosomal stress as common liabilities of aneuploid cancers.
| S-EPMC11914506 | biostudies-literature
Project description:Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a meta-analysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly-related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, while genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical anti-proliferative response that must be overcome prior to transformation. These experiments are two-color hybridizations of RNA isolated from aneuploid samples vs matched wt cells, all grown to midlog phase.
2012-06-28 | E-GEOD-35853 | biostudies-arrayexpress
Project description:Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a meta-analysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly-related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, while genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical anti-proliferative response that must be overcome prior to transformation.
2012-06-29 | GSE35853 | GEO
Project description:Aneuploidy is prevalent in cancer, conferring fitness advantage, multidrug resistance, and poor prognosis. In contrast, experimentally induced aneuploidy often results in adverse effects and impaired proliferation. This paradox underscores the necessity of cancer cells to adapt to abnormal chromosome numbers. To identify molecular mechanisms of adaptation to aneuploidy, we initiated in vitro evolution of cells with extra chromosomes added via microcell-mediated chromosome transfer. To this end, we cultured cells in a nutrient-rich medium for 50 passages or plated the cells at a low density and selectively collected the largest colonies originating from a single cell (colony selection). The anaylsis global proteoms of the evolved cell lines was then carried out using TMT quantification strategy. This dataset also includes measurements from post-xenograft aneuploid cell line.
2025-01-14 | PXD049120 | Pride
Project description:Aneuploidy is prevalent in cancer, conferring fitness advantage, multidrug resistance, and poor prognosis. In contrast, experimentally induced aneuploidy often results in adverse effects and impaired proliferation. This paradox underscores the necessity of cancer cells to adapt to abnormal chromosome numbers. To identify molecular mechanisms of adaptation to aneuploidy, we initiated in vitro evolution of cells with extra chromosomes added via microcell-mediated chromosome transfer. To this end, we cultured cells in a nutrient-rich medium for 50 passages or plated the cells at a low density and selectively collected the largest colonies originating from a single cell (colony selection). The anaylsis of global proteomes of the evolved cell lines was then carried out using a TMT quantification strategy. This data set also includes data from trisomic cells with and without TP53 k.o.
2025-01-14 | PXD049124 | Pride
Project description:Aneuploidy is prevalent in cancer, conferring fitness advantage, multidrug resistance, and poor prognosis. In contrast, experimentally induced aneuploidy often results in adverse effects and impaired proliferation. This paradox underscores the necessity of cancer cells to adapt to abnormal chromosome numbers. To identify molecular mechanisms of adaptation to aneuploidy, we initiated in vitro evolution of cells with extra chromosomes added via microcell-mediated chromosome transfer. To this end, we cultured cells in a nutrient-rich medium for 50 passages or plated the cells at a low density and selectively collected the largest colonies originating from a single cell (colony selection). One of the striking observations following evolution of cells with extra chromosome 5 in HCT116 cell line was the frequent loss of the 5q, while maintaining the 5p arm after in vitro evolution. Chromosome 5 is a frequent target of large copy number alterations in several malignancies, such as ovarian, gastric, and oesophageal cancer, and malignant myeloid diseases. Moreover, analysis of chromosome arm level events in the TCGA dataset clearly shows that loss of chromosome arm 5q and gain of 5p are among the most frequent events. We asked whether these specific changes in copy numbers of chromosome 5 – loss of 5q with simultaneous retention of 5p – could affect the proliferation of the evolved cells. To this end, we used the recently developed technique ReDACT-TR (Restoring Disomy in Aneuploid cells using CRISPR Targeting with Telomere Replacement (Girish et al., 2023)), and transfected cells of a separate clone of Htr5 (before evolution) with a gRNA that cuts near the centromere of chromosome 5, simultaneously with a cassette encoding ~100 repeats of the human telomere seed sequence. Targeting the q-arm generated two independent cell lines with 5p trisomy (Htr5p_1 and Htr5p_2), which were confirmed by FISH with probes specific for 5p and 5q arms and by shallow WGS. No cell lines with trisomy of the q-arm were generated, but we have obtained two diploid cell lines (Hdi5_1 and Hdi5_2), most likely due to the CRISPR/Cas9 induced loss of chromosome 5 (Papathanasiou, Markoulaki et al., 2021, Tsuchida, Brandes et al., 2023). The anaylsis of global proteomes of the ReDACT cell lines was then carried out using a TMT quantification strategy.
2025-01-14 | PXD056432 | Pride
Project description:Consequences of aneuploidy in human fibroblasts with trisomy 21
| PRJNA646219 | ENA