Rui Wang

Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma

Ovarian cancer is the sixth leading cause of cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated via Ovgp1 -driven Cre recombinase effecting CRISPR/Cas9-mediated deletion of Trp53, Rb1 , and Nf1 tumor suppressors in mouse oviductal epithelium ( m-sgPRN model). Cyclin-dependent kinase 12 (CDK12) inactivation—frequently observed in human HGSC—is associated with poorer outcomes, DNA damage accumulation (including tandem duplications), and increased tumor immunogenicity. In our system, coablation of Cdk12 ( m-sgPRN;Cdk12KO ) recapitulated hallmark features of HGSC, while accelerating tumor progression and reducing survival. In a conventional (Cre-lox-mediated) Trp53/Nf1/Rb1 triple knockout model with concurrent Cdk12 ablation ( PRN ; Cdk12KO mice), we observed T cell–rich immune infiltrates mirroring those seen clinically. We established both models as subcutaneous or intraperitoneal syngeneic allografts of CDK12 -inactivated HGSC that exhibited sensitivity to immune checkpoint blockade. Furthermore, a CRISPR/Cas9 synthetic lethality screen in PRN;Cdk12KO -derived cell lines identified CDK13—an essential paralog of CDK12—as the most depleted candidate, confirming a previously reported synthetic lethal interaction. Pharmacologic CDK13/12 degradation (employing YJ1206) demonstrated enhanced efficacy in cell lines derived from both m-sgPRN;Cdk12KO and PRN ; Cdk12KO models. Our results define CDK12 as a key tumor suppressor in tubo-ovarian HGSC and highlight CDK13 targeting as a promising therapeutic approach in CDK12 -inactive disease. Additionally, we have established valuable in vivo resources to facilitate further investigation and drug development in this challenging malignancy.

Prediction of the survival of patients with advanced‐stage ovarian cancer patients undergoing interval cytoreduction with the use of computed tomography reevaluation after neoadjuvant chemotherapy

AbstractPurposeTo predict ovarian cancer patients' survival by computed tomography (CT) reevaluation after neoadjuvant chemotherapy.Patients and MethodsIn this retrospective single‐center cohort study, all patients with advanced epithelial ovarian cancer underwent platinum‐based chemotherapy followed by interval cytoreductive surgery. Assessment of abdominal and pelvic lesions before and after chemotherapy using CT scoring criteria. Meanwhile, the progression‐free survival and overall survival times were obtained. The Kaplan–Meier method was used to estimate survival curves. Univariate analysis of continuous and categorical variables was performed for prognostic significance using the Cox proportional hazards model. Variables with p < 0.10 on univariate analysis were then included in a multivariate forward stepwise Cox regression analysis.ResultsA total of 162 patients were included, with a median age of 52 years (range, 20–72 years). One hundred seven patients (66.0%) underwent suboptimal cytoreduction, and there was no statistically significant difference in patient survival between surgical procedures (log‐rank p = 0.092). Six radiographic features were hazard factors for suboptimal cytoreduction. Four features in the postchemotherapy CT images were assigned as predictive criteria by the stepwise regression model (area under the curve [AUC] = 0.689). As compared with a higher AUC (0.713) in the model involving two clinical variables (age and postsurgery CA‐125) and two postchemotherapy CT features, the model considering the CT score changes before and after chemotherapy had the highest diagnostic accuracy (AUC = 0.843).ConclusionCT reevaluation after neoadjuvant chemotherapy is essential for ovarian cancer, the changes of CT feature and score are potential great tools to predict patient survival.

Mixed germ cell tumors metastasis to Ascitic fluid: Report of a case with immunocytochemical findings

CircMYBL2 regulates the resistance of cervical cancer cells to paclitaxel via miR‐665‐dependent regulation of EGFR

AbstractCircular RNAs are considered to be associated with cancer resistance. This study aims to investigate the function and mechanism of circMYBL2 in paclitaxel (PTX) resistance of cervical cancer (CC). The expression of circMYBL2, miR‐665 and epidermal growth factor receptor (EGFR) was investigated using quantitative real‐time polymerase chain reaction assay. Cell viability, cell colony number, cell proliferation, apoptosis and lactate dehydrogenase (LDH) were detected by 3‐(4, 5‐Dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide, colony formation, 5‐ethynyl‐2′‐deoxyuridine incorporation, flow cytometry and LDH release assays, respectively. The interaction between miR‐665 and circMYBL2 or EGFR was confirmed by dual‐luciferase reporter assay. The protein expression levels were quantified by western blot or immunohistochemistry assay. Mice xenograft models were constructed to investigate the effect of circMYBL2 on CC tumor growth. CircMYBL2 was upregulated in CC tissues and cells, especially in PTX‐resistant CC tissues and cells, and it was a stable circRNA mainly distributed in the cytoplasm. CircMYBL2 could enhance the PTX resistance of CC cells in vitro and promote CC tumor growth in vivo. Mechanistically, circMYBL2 could inhibit the PTX sensitivity and promote cell malignant behaviors in PTX‐sensitive and PTX‐resistant CC cells via upregulating EGFR mediated by miR‐665. CircMYBL2 played a positive role in the PTX resistance and malignant activities of PTX‐sensitive and PTX‐resistant CC cells by regulating the miR‐665/EGFR network, providing a novel therapeutic strategy for the treatment of CC patients resistant to PTX.