Biology subjects

Villamor, E.

Publications and source records attributed to Villamor, E..

4 recordsLinked to original sources

bioRxiv2026

Metallothionein loss in cancer cells contributes to increased mutations through defective DNA repair and metabolic imbalance

Understanding which genes are involved in mutagenesis is essential for developing cancer prevention and treatment strategies; establishing protectors of the genome has revolutionized cancer biology. Here, we describe metallothionein (MT) proteins as previously uncharacterized protectors against mutagenesis. MT is a heavy metal binding protein essential for zinc homeostasis and protection against heavy metal cytotoxicity. Because zinc binds approximately 10-15% of the proteome and is critical for processes such as DNA repair and mitochondrial health, MT loss is expected to disrupt these processes. We hypothesized that MT loss induces genomic instability by impairing DNA repair and mitochondrial function. In this study, the consequences of MT deficiency in high-grade serous ovarian cancer (HGSC) were investigated by knockdown of the most highly expressed MT, MT2A. Loss of MT2A resulted in the impaired DNA repair pathway base excision repair (BER), leading to increased mutagenesis. MT2A deficiency produced mitochondrial dysfunction, characterized by a decrease in mitochondrial membrane potential, glycolysis, oxidative phosphorylation, amino acids, and an imbalance of nucleobases. Together, these defects reflect cellular states associated with increased cancer aggressiveness. These findings identify MT as a fundamental hub maintaining genomic and metabolic integrity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/736843v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1af4adeorg.highwire.dtl.DTLVardef@15c588forg.highwire.dtl.DTLVardef@1ba5181org.highwire.dtl.DTLVardef@13d150b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

MYC is sufficient to generate mid-life high-grade serous ovarian and uterine serous carcinomas in a p53-R270H mouse model

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. However, previous GEMMs of high-grade serous ovarian cancer (HGSOC) have had to utilize genetics rarely or never found in human HGSOC to yield ovarian cancer within the lifespan of a mouse. MYC, an oncogene, is amongst the most amplified genes in HGSOC, but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate the Myc and Trp53-R270H transgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the fallopian tube epithelium.

cancer biology↗

bioRxiv2018

Chorioamnionitis Is a Risk Factor for Intraventricular Hemorrhage in Preterm Infants: A Systematic Review and Meta-Analysis

Although chorioamnionitis (CA) is a well-known risk factor for white matter disease of prematurity, the association with intraventricular hemorrhage (IVH) is controversial and has not been yet systematically reviewed. We performed a systematic review and meta-analysis of studies exploring the association between CA and IVH. A comprehensive literature search was conducted using PubMed/MEDLINE and EMBASE, from their inception to 1 July 2017. Studies were included if they examined preterm infants and reported primary data that could be used to measure the association between exposure to CA and the presence of IVH. A random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). We found 1284 potentially relevant studies, of which 85 met the inclusion criteria (46,244 infants, 13,432 CA cases). Meta-analysis showed that CA exposure was significantly associated with all grades IVH (OR 1.88, 95% CI 1.61-2.19), with grades 1-2 IVH (OR 1.69, 95% CI 1.22-2.34), and with grades 3-4 IVH (OR 1.62, 95% CI 1.42-1.85). Both clinical and histological CA were associated with an increased risk for developing IVH in very preterm infants. In contrast, the presence of funisitis did not increase IVH risk when compared to CA in the absence of funisitis (OR 1.22, 95% CI 0.89-1.67). Further meta-analyses confirmed earlier findings that CA-exposed infants have significantly lower gestation age (GA; mean difference [MD] -1.20 weeks) and lower birth weight (BW; MD -55g) than the infants not exposed to CA. However, meta-regression and subgroup analysis could not demonstrate an association between the lower GA and BW and the risk of IVH in the CA-exposed infants. In conclusion, our data show that CA is a risk factor for IVH, but also a risk factor for greater prematurity and more clinical instability. In contrast to other complications of prematurity, such as patent ductus arteriosus, retinopathy of prematurity, or bronchopulmonary dysplasia, the effect of CA on IVH appears to be independent of CA as causative factor for very preterm birth.

developmental biology↗

bioRxiv2018

Chorioamnionitis as a risk factor for retinopathy of prematurity: an updated systematic review and meta-analysis

The role of chorioamnionitis (CA) in the development of retinopathy of prematurity (ROP) is difficult to establish, because CA-exposed and CA-unexposed infants frequently present different baseline characteristics. We performed an updated systematic review and meta-analysis of studies reporting on the association between CA and ROP. We searched PubMed and EMBASE for relevant articles. Studies were included if they examined preterm or very low birth weight (VLBW, <1500g) infants and reported primary data that could be used to measure the association between exposure to CA and the presence of ROP. Of 748 potentially relevant studies, 50 studies met the inclusion criteria (38,986 infants, 9,258 CA cases). Meta-analysis showed a significant positive association between CA and any stage ROP (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.11 to 1.74). CA was also associated with severe (stage [≥]3) ROP (OR 1.63, 95% CI 1.41 to 1.89). Exposure to funisitis was associated with a higher risk of ROP than exposure to CA in the absence of funisitis. Additional meta-analyses showed that infants exposed to CA had lower gestational age (GA) and lower birth weight (BW). Meta-regression showed that lower GA and BW in the CA-exposed group was significantly associated with a higher risk of ROP. In conclusion, our study confirms that CA is a risk factor for developing ROP. However, part of the effects of CA on the pathogenesis of ROP may be mediated by the role of CA as an etiological factor for very preterm birth.

epidemiology↗