Biology subjects

Lomonosova, E.

Publications and source records attributed to Lomonosova, E..

5 recordsLinked to original sources

bioRxiv2026

3D Printed Bioelectronic Scaffolds for Impedance-based Cytotoxicity Monitoring of In Vitro Cancer Models

Cancer is a significant contributor to global mortality and places a substantial burden on healthcare systems, underscoring the need for improved strategies for developing and evaluating new therapies. Electrochemical impedance monitoring of in vitro cancer models is a promising technique for evaluating treatment effectiveness, particularly for evaluating how well a drug may kill cancer cells. This approach is advantageous over conventional end-point assays because it is non-destructive, label-free, and can provide temporal information on cell behavior and drug kinetics. However, traditional impedance devices are limited in that they do not support three-dimensional cell culture that has become standard in cancer studies. Typical devices are planar substrates that support monolayer culture, which has been shown to overestimate drug effectiveness. In this work, we propose 3D printed bioelectronic scaffold devices that provide 3D cancer cell culture while functioning as an on-chip readout for monitoring changes in cell characteristics via impedance. We describe device development and demonstrate reproducible fabrication, stable electrochemical properties, cell detection by impedance, and proof-of-concept monitoring of cytotoxicity in response to a chemotherapeutic drug. Overall, this technology offers a promising platform that could be further developed for compound screening as part of drug development or precision medicine.

bioengineering↗

bioRxiv2025

Targeting ALC1 can safely expand the therapeutic utility of PARP inhibitors across high-grade serous ovarian cancers

Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for homologous recombination-deficient (HRD) high-grade serous ovarian cancers (HGSOCs), but their long-term effectiveness is limited by the emergence of resistance and hematological toxicity. Moreover, PARPi are largely ineffective in HR-proficient HGSOCs, particularly tumors with CCNE1 amplification, which exhibit marked therapeutic resistance and currently lack effective treatment options. Loss of a chromatin remodeling enzyme, Amplified in Liver Cancer 1 (ALC1), has been shown to enhance PARPi sensitivity. However, the clinical contexts in which ALC1 targeting will be clinically meaningful remain elusive. Here we demonstrate that ALC1 loss enhances PARPi sensitivity across HRD and CCNE1-amplified serous ovarian cancer lines, xenograft and patient-derived cells. ALC1 depletion can overcome clinically relevant mechanisms of PARPi resistance while having minimal effects in BRCA-wild-type or heterozygous non-cancerous cells. Consistent with this therapeutic safety, PARPi sensitivity upon ALC1 loss can be reliably predicted by the endogenous levels of phospho-T21 RPA2, a marker for replication stress which is typically higher in ovarian cancer cells compared to their normal counterparts. Together, our studies define the clinical contexts in which the therapeutic utility of PARPi can be expanded by targeting ALC1, whose inhibitors are currently in Phase I clinical trials.

cancer biology↗

bioRxiv2025

Targeting the COP9 signalosome overcomes platinum resistance in ovarian cancer through two distinct genome stability mechanisms

Tubo-ovarian high-grade serous carcinoma (HGSC) is a leading cause of gynecologic cancer mortality, largely due to the emergence of platinum resistance, which serves as the mainstay of chemotherapy. Here, we identify COPS5 as a therapeutic target and use an available small molecule inhibitor to overcome platinum resistance. A genetic screen for platinum-induced DNA damage in a platinum resistant ovarian cancer model identified COPS5 and COPS6, two components of the COP9 signalosome. Consistently, high COPS5 expression correlated with poor clinical outcomes in patients with HGSC. In both in vitro and in vivo experiments, COPS5 depletion sensitized ovarian cancer cells to carboplatin. A small molecule COPS5 inhibitor, CSN5i-3, synergized with carboplatin in homologous recombination-deficient and -proficient cells. This combination was also effective in xenografts and in a syngeneic mouse model of carboplatin-resistant HGSC. Importantly, we demonstrate that CSN5i-3 is selective for cancer cells, with patient-derived HGSC cells exhibiting up to 50-fold greater sensitivity to CSN5i-3 than benign cells. Finally, we show that genetic or small molecule inhibition of COPS5 impaired both nucleotide excision repair (NER) and interstrand crosslink (ICL) repair, leading to increased DNA platinum adducts. Mechanistically, this was due to increased ubiquitination and degradation of DNA-specific DNA binding protein 1 (DDB1) and other key NER and ICL repair proteins, consistent with the role of COPS5 in the regulation of these factors. Our findings highlight the importance of NER and ICL regulation in chemotherapy response and indicate that targeting COPS5 can enhance the efficacy of platinum-based chemotherapy in HGSC. One Sentence SummaryCOPS5 depletion or inhibition using a small molecule COPS5 inhibitor CSN5i-3 sensitizes high-grade serous carcinoma to platinum chemotherapy through downregulation of nucleotide excision repair and interstrand crosslink repair.

cancer biology↗

bioRxiv2024

Replication stress marker phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination-proficient ovarian cancer

BackgroundOvarian cancer treatment includes cytoreductive surgery, platinum-based chemotherapy, and often poly (ADP-ribose) polymerase (PARP) inhibitors. Homologous recombination (HR)-deficiency is a well-established predictor of therapy sensitivity. However, over 50% of HR-proficient tumors also exhibit sensitivity to standard-of-care treatments. Currently, there are no biomarkers to identify which HR-proficient tumors will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. MethodsWe evaluated phospho-RPA2-T21 (pRPA2) foci via immunofluorescence as a potential biomarker of replication stress in formalin-fixed, paraffin-embedded tumor samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort: n = 31, validation cohort: n = 244) or PARP inhibitors (n = 87). Recurrent tumors (n = 37) were also analyzed. pRPA2 scores were calculated using automated imaging analysis. Samples were defined as pRPA2-High if > 16% of cells had [≥] 2 pRPA2 foci. ResultsIn the discovery cohort, HR-proficient, pRPA2-High tumors demonstrated significantly higher rates of pathologic complete response to platinum chemotherapy than HR-proficient, pRPA2-Low tumors. In the validation cohort, patients with HR-proficient, pRPA2-High tumors had significantly longer survival after platinum treatment than those with HR-proficient, pRPA2-Low tumors. Additionally, the pRPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent tumor samples. ConclusionOur study underscores the importance of considering replication stress markers alongside HR status in therapeutic planning. Our work suggest that this assay could be used throughout a patients treatment course to expand the number of patients receiving effective therapy while reducing unnecessary toxicity.

cancer biology↗

bioRxiv2024

Single Nuclei Sequencing Reveals Replication Stress in Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and limited treatment options. Bulk genomic characterization of ACC has not yielded obvious therapeutic or immunotherapeutic targets, yet novel therapies are needed. We hypothesized that elucidating the intratumoral cellular heterogeneity by single nuclei RNA sequencing analyses would yield insights into potential therapeutic vulnerabilities of this disease. In addition to characterizing the immune cell and fibroblast landscape, our analyses of single nuclei gene expression profiles identified an adrenal cortex cell cluster exhibiting a program of replication stress and DNA damage response in primary and metastatic ACC. In vitro assessment of replication stress and DNA damage response using an ACC cell line and a series of newly-derived hormonally active patient-derived tumor organoids revealed ATR sensitivity. These findings provide novel mechanistic insight into ACC biology and suggest that an underlying dependency on ATR may be leveraged therapeutically in advanced ACC.

cancer biology↗