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1.
NAR Cancer ; 6(3): zcae030, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39015544

RESUMO

A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of TIMELESS, a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analysed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork stalling, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential. Importantly nucleoside supplementation restores PARG inhibitor resistance despite the continued presence of PAR chains, indicating that sensitivity does not correlate with PAR levels. In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.

2.
Nature ; 618(7967): 1041-1048, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37165191

RESUMO

Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis1-5. As each chromosome contains a single centromere, it remains unclear how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis6. Here we tracked micronucleated chromosomes with live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for asymmetric inheritance by a single daughter cell. Mechanistically, the CIP2A-TOPBP1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises pulverized chromosomes for clustering upon mitotic entry. Inactivation of CIP2A-TOPBP1 caused acentric fragments to disperse throughout the mitotic cytoplasm, stochastically partition into the nucleus of both daughter cells and aberrantly misaccumulate as cytoplasmic DNA. Mitotic clustering facilitates the reassembly of acentric fragments into rearranged chromosomes lacking the extensive DNA copy-number losses that are characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer genomes revealed clusters of DNA copy-number-neutral rearrangements-termed balanced chromothripsis-across diverse tumour types resulting in the acquisition of known cancer driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial clustering of pulverized chromosomes from micronuclei.


Assuntos
Cromossomos Humanos , Cromotripsia , Micronúcleos com Defeito Cromossômico , Mitose , Humanos , Centrômero , Cromossomos Humanos/genética , DNA/genética , DNA/metabolismo , Variações do Número de Cópias de DNA , Interfase , Mitose/genética , Neoplasias/genética
3.
Dis Model Mech ; 14(11)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34569598

RESUMO

High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). However, direct causes of CIN, such as mutations in DNA replication and mitosis genes, are rare in HGSOC. We therefore asked whether oncogenic mutations that are common in HGSOC can indirectly drive CIN in non-transformed human fallopian tube epithelial cells. To model homologous recombination deficient HGSOC, we sequentially mutated TP53 and BRCA1 then overexpressed MYC. Loss of p53 function alone was sufficient to drive the emergence of subclonal karyotype alterations. TP53 mutation also led to global gene expression changes, influencing modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function. Both transcriptional deregulation and karyotype diversity were exacerbated by loss of BRCA1 function, with whole-genome doubling events observed in independent p53/BRCA1-deficient lineages. Thus, our observations indicate that loss of the key tumour suppressor TP53 is sufficient to deregulate multiple cell cycle control networks and thereby initiate CIN in pre-malignant fallopian tube epithelial cells. This article has an associated First Person interview with the first author of the paper.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Instabilidade Cromossômica , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Células Epiteliais/metabolismo , Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Feminino , Humanos , Mutação/genética , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Genome Med ; 13(1): 93, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034815

RESUMO

BACKGROUND: Many carcinomas have recurrent chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is not completely understood. METHODS: In this study, we looked at the frequency of chromosomal arm gains and losses in different cancer types from the The Cancer Genome Atlas (TCGA) and compared them to the mean gene expression of each chromosome arm in corresponding normal tissues of origin from the Genotype-Tissue Expression (GTEx) database, in addition to the distribution of tissue-specific oncogenes and tumor suppressors on different chromosome arms. RESULTS: This analysis revealed a complex picture of factors driving tumor karyotype evolution in which some recurrent chromosomal copy number reflect the chromosome arm-wide gene expression levels of the their normal tissue of tumor origin. CONCLUSIONS: We conclude that the cancer type-specific distribution of chromosomal arm gains and losses is potentially "hardwiring" gene expression levels characteristic of the normal tissue of tumor origin, in addition to broadly modulating the expression of tissue-specific tumor driver genes.


Assuntos
Aneuploidia , Biomarcadores Tumorais , Mapeamento Cromossômico , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Algoritmos , Análise por Conglomerados , Biologia Computacional/métodos , Metilação de DNA , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Mutação , Oncogenes , Especificidade de Órgãos/genética
5.
EMBO Mol Med ; 12(3): e12017, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32072755

RESUMO

Oncogene-addicted tumors present a valuable target for therapeutic intervention and an opportunity to achieve a wide therapeutic window. Nonetheless, resistance to targeted therapies is frequently observed and it arises through multiple mechanisms, including mutations in the target gene. Chromosomal instability, a defining feature of human cancer, has been linked to targeted therapy resistance, but the mechanism underlying this association is poorly understood. In the current issue of EMBO Molecular Medicine, Salgueiro et al show that chromosomal instability can lead to the generation of alternative oncogenic drivers, thereby providing the ability for cancer cells to overcome the oncogene withdrawal bottleneck. Importantly, this study shows that, by generating de novo genomic diversity, chromosomal instability serves as an adaptive response to therapeutic insult.


Assuntos
Neoplasias , Vício Oncogênico , Instabilidade Cromossômica , Genômica , Humanos , Neoplasias/genética , Oncogenes
6.
Cell Rep ; 25(3): 749-760.e6, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332653

RESUMO

Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1α and that inhibiting Hif-1α restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1α to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.


Assuntos
Aneuploidia , Apoptose , Cromossomos Humanos/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Sistemas CRISPR-Cas , Neoplasias do Colo , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Transdução de Sinais , Células Tumorais Cultivadas
7.
Carcinogenesis ; 39(8): 993-1005, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-29800151

RESUMO

Intratumor heterogeneity is a major challenge in cancer treatment. To decipher patterns of chromosomal heterogeneity, we analyzed six colorectal cancer cell lines by multiplex interphase FISH (miFISH). The mismatch-repair-deficient cell lines DLD-1 and HCT116 had the most stable copy numbers, whereas aneuploid cell lines (HT-29, SW480, SW620 and H508) displayed a higher degree of instability. We subsequently assessed the clonal evolution of single cells in two colorectal carcinoma cell lines, SW480 and HT-29, which both have aneuploid karyotypes but different degrees of chromosomal instability. The clonal compositions of the single cell-derived daughter lines, as assessed by miFISH, differed for HT-29 and SW480. Daughters of HT-29 were stable, clonal, with little heterogeneity. Daughters of SW480 were more heterogeneous, with the single cell-derived daughter lines separating into two distinct populations with different ploidy (hyper-diploid and near-triploid), morphology, gene expression and tumorigenicity. To better understand the evolutionary trajectory for the two SW480 populations, we constructed phylogenetic trees which showed ongoing instability in the daughter lines. When analyzing the evolutionary development over time, most single cell-derived daughter lines maintained their major clonal pattern, with the exception of one daughter line that showed a switch involving a loss of APC. Our meticulous analysis of the clonal evolution and composition of these colorectal cancer models shows that all chromosomes are subject to segregation errors, however, specific net genomic imbalances are maintained. Karyotype evolution is driven by the necessity to arrive at and maintain a specific plateau of chromosomal copy numbers as the drivers of carcinogenesis.


Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Evolução Molecular , Linhagem Celular Tumoral , Instabilidade Cromossômica , Aberrações Cromossômicas , Evolução Clonal , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Cariótipo , Filogenia
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