NAR cancer最新文献

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection. Analysis of BRCA1/2 status showed that in our cohort of 31 ovarian cancer PDX models 22.6% harbored a BRCA1/2 alteration (7/31), and 48.3% (15/31) were genomically unstable as measured by copy number alteration analysis. In vivo, PARPi olaparib response was measured in 15 selected PDX models. Functional assessment of HR using ex vivo irradiation-induced RAD51 foci formation identified all olaparib-sensitive PDX models, including four models without BRCA1/2 alterations. In contrast, replication fork protection or replication speed in ex vivo tumor tissue did not correlate with olaparib response. Targeted panel sequencing in olaparib-sensitive models lacking BRCA1/2 alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that ex vivo RAD51 analysis effectively predicts in vivo olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.

Aberrant expression of the BAP1 (BRCA associated protein 1) tumor suppressor gene is a prominent risk factor for several tumor types and is important in tumor evolution and progression. Here we performed integrated multi-omics analyses using data from The Cancer Genome Atlas for 33 cancer types and over 10 000 individuals to identify alterations leading to BAP1 disruption. We combined existing variant calls and new calls derived from a de novo local realignment pipeline across multiple independent variant callers, increasing somatic variant detection by 41% from 182 to 257, including 11 indels ≥40 bp. The expanded detection of mutations highlights the power of new tools to uncover longer indels and impactful mutations. We developed an expression-based BAP1 activity score and identified a transcriptional profile associated with BAP1 disruption in cancer. BAP1 has been proposed to play a critical role in controlling tumor plasticity and normal cell fate. Leveraging human and mouse liver datasets, BAP1 loss in normal cells resulted in lower BAP1 activity scores and lower scores were associated with a less-differentiated phenotype in embryonic cells. Together, our expanded BAP1 mutant samples revealed a transcriptional signature in cancer cells, supporting BAP1's influences on cellular plasticity and cell identity maintenance.

Cancer is a disease underpinned by aberrant gene expression. Enhancers are regulatory elements that play a major role in transcriptional control and changes in active enhancer function are likely critical in the pathogenesis of oesophageal adenocarcinoma (OAC). Here, we utilise STARR-seq to profile the genome-wide enhancer landscape in OAC and identify hundreds of high-confidence enhancer elements. These regions are enriched in enhancer-associated chromatin marks, are actively transcribed and exhibit high levels of associated gene activity in OAC cells. These characteristics are maintained in human patient samples, demonstrating their disease relevance. This relevance is further underlined by their responsiveness to oncogenic ERBB2 inhibition and increased activity compared to the pre-cancerous Barrett's state. Mechanistically, these enhancers are linked to the core OAC transcriptional network and in particular KLF5 binding is associated with high level activity, providing further support for a role of this transcription factor in defining the OAC transcriptome. Our results therefore uncover a set of enhancer elements with physiological significance, that widen our understanding of the molecular alterations in OAC and point to mechanisms through which response to targeted therapy may occur.

The p53 tumor suppressor gene governs a multitude of complex cellular processes that are essential for anti-cancer function and whose dysregulation leads to aberrant gene transcription, activation of oncogenic signaling and cancer development. Although mutations can occur at any point in the genetic sequence, missense mutations comprise the majority of observed p53 mutations in cancers regardless of whether the mutation is germline or somatic. One biological process involved in both mutant and wild-type p53 signaling is the N ⁶-methyladenosine (m⁶A) epitranscriptomic network, a type of post-transcriptional modification involved in over half of all eukaryotic mRNAs. Recently, a significant number of findings have demonstrated unique interactions between p53 and the m⁶A epitranscriptomic network in a variety of cancer types, shedding light on a previously uncharacterized connection that causes significant dysregulation. Cross-talk between wild-type or mutant p53 and the m⁶A readers, writers and erasers has been shown to impact cellular function and induce cancer formation by influencing various cancer hallmarks. Here, this review aims to summarize the complex interplay between the m⁶A epitranscriptome and p53 signaling pathway, highlighting its effects on tumorigenesis and other hallmarks of cancer, as well as identifying its therapeutic implications for the future.

Bisphenol A (BPA) is a phenolic chemical that has been used for over 50 years in the manufacturing of polycarbonate and polyvinyl chloride plastics, and it is one of the highest volume chemicals produced worldwide. Because BPA can bind to and activate estrogen receptors, studies have mainly focused on the effect of BPA in disrupting the human endocrine and reproductive systems. However, BPA also plays a role in promoting genomic instability and has been associated with initiating carcinogenesis. For example, it has been recently shown that exposure to BPA promotes the formation of single stranded DNA gaps, which may be associated with increased genomic instability. In this review, we outline the mechanisms by which BPA works to promote genomic instability including chromosomal instability, DNA adduct formation, ROS production, and estrogen receptor (ER) activation. Moreover, we define the ways in which BPA promotes both carcinogenesis and resistance to chemotherapy, and we provide critical insights into future directions and outstanding questions in the field.

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.

Somatic mutations are desirable targets for selective elimination of cancer, yet most are found within noncoding regions. We have adapted the CRISPR-Cas9 gene editing tool as a novel, cancer-specific killing strategy by targeting the subset of somatic mutations that create protospacer adjacent motifs (PAMs), which have evolutionally allowed bacterial cells to distinguish between self and non-self DNA for Cas9-induced double strand breaks. Whole genome sequencing (WGS) of paired tumor minus normal (T-N) samples from three pancreatic cancer patients (Panc480, Panc504, and Panc1002) showed an average of 417 somatic PAMs per tumor produced from single base substitutions. Further analyses of 591 paired T-N samples from The International Cancer Genome Consortium found medians of ∼455 somatic PAMs per tumor in pancreatic, ∼2800 in lung, and ∼3200 in esophageal cancer cohorts. Finally, we demonstrated 69-99% selective cell death of three targeted pancreatic cancer cell lines using 4-9 sgRNAs designed using the somatic PAM discovery approach. We also showed no off-target activity from these tumor-specific sgRNAs in either the patient's normal cells or an irrelevant cancer using WGS. This study demonstrates the potential of CRISPR-Cas9 as a novel and selective anti-cancer strategy, and supports the genetic targeting of adult cancers.

Extrachromosomal circular DNAs (eccDNAs) are produced from all regions of the eucaryotic genome. We used inverse PCR of non-B microsatellites capable of forming hairpin, triplex, quadruplex and AT-rich structures integrated at a common ectopic chromosomal site to show that these non-B DNAs generate highly mutagenized eccDNAs by replication-dependent mechanisms. Mutagenesis occurs within the non-B DNAs and extends several kilobases bidirectionally into flanking and nonallelic DNA. Each non-B DNA exhibits a different pattern of mutagenesis, while sister clones containing the same non-B DNA also display distinct patterns of recombination, microhomology-mediated template switching and base substitutions. Mutations include mismatches, short duplications, long nontemplated insertions, large deletions and template switches to sister chromatids and nonallelic chromosomes. Drug-induced replication stress or the depletion of DNA repair factors Rad51, the COPS2 signalosome subunit or POLη change the pattern of template switching and alter the eccDNA mutagenic profiles. We propose an asynchronous capture model based on break-induced replication from microsatellite-induced DNA double strand breaks to account for the generation and circularization of mutagenized eccDNAs and the appearance of genomic homologous recombination deficiency (HRD) scars. These results may help to explain the appearance of tumor eccDNAS and their roles in neoantigen production, oncogenesis and resistance to chemotherapy.

Translational reprogramming in response to oncogenic signaling or microenvironmental stress factors shapes the proteome of cancer cells, enabling adaptation and phenotypic changes underlying cell plasticity, tumor progression and response to cancer therapy. Among the mechanisms regulating translation are RNA G-quadruplexes (RG4s), non-canonical four-stranded structures whose conformational modulation by small molecule ligands and RNA-binding proteins affects the expression of cancer proteins. Here, we discuss the role of RG4s in the regulation of mRNA translation by focusing on paradigmatic examples showing their contribution to adaptive mechanisms of mRNA translation in cancer.

The now well described canonical mRNA translation initiation mechanism of m⁷G 'cap' recognition by cap-binding protein eIF4E and assembly of the canonical pre-initiation complex consisting of scaffolding protein eIF4G and RNA helicase eIF4A has historically been thought to describe all cellular mRNA translation. However, the past decade has seen the discovery of alternative mechanisms to canonical eIF4E mediated mRNA translation initiation. Studies have shown that non-canonical alternate mechanisms of cellular mRNA translation initiation, whether cap-dependent or independent, serve to provide selective translation of mRNAs under cell physiological and pathological stress conditions. These conditions typically involve the global downregulation of canonical eIF4E1/cap-mediated mRNA translation, and selective translational reprogramming of the cell proteome, as occurs in tumor development and malignant progression. Cancer cells must be able to maintain physiological plasticity to acquire a migratory phenotype, invade tissues, metastasize, survive and adapt to severe microenvironmental stress conditions that involve inhibition of canonical mRNA translation initiation. In this review we describe the emerging, important role of non-canonical, alternate mechanisms of mRNA translation initiation in cancer, particularly in adaptation to stresses and the phenotypic cell fate changes involved in malignant progression and metastasis. These alternate translation initiation mechanisms provide new targets for oncology therapeutics development.