Lin Zhang

Repression of PRMT activities sensitize human homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment

Therapeutic epigenetic modulation is currently being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARP inhibitors. To broaden its clinical applicability and identify more effective combination strategies, we conducted a drug screen combining PARP inhibitors with 74 well-characterized epigenetic modulators targeting five major classes of epigenetic enzymes. Notably, both type I PRMT inhibitors and PRMT5 inhibitors scored highly in combination efficacy and clinical prioritization. PRMT inhibition significantly enhanced PARP inhibitor-induced DNA damage in human HR-proficient ovarian and breast cancer cells. Mechanistically, PRMT suppression downregulates DNA damage repair genes and BRCAness-associated pathways, while also modulating intrinsic innate immune responses within cancer cells. Integrative analysis of large-scale genomic and functional datasets from TCGA and DepMap further supports PRMT1, PRMT4, and PRMT5 as promising therapeutic targets in oncology. Importantly, dual inhibition of PRMT1 and PRMT5 synergistically sensitizes tumors to PARP inhibitors. Collectively, our findings provide strong rationale for the clinical development of PRMT and PARP inhibitor combinations in HR-proficient ovarian and breast cancers.

IL7R remodels immunosuppression tumor microenvironment and promotes macrophage polarization by regulating NF-κB/CXCL1 axis in ovarian cancer

Abstract In the ovarian cancer microenvironment, the polarization of tumor-associated macrophages (TAMs) is closely associated with immunosuppressive phenotypes. Although elevated levels of circulating interleukin-7 (IL-7) have been linked to a poor prognosis, the regulatory mechanisms underlying this association remain incompletely understood. This study demonstrated that increased IL7R expression in ovarian cancer is correlated with the polarization of CD206 + macrophages, the remodeling of the immunosuppressive microenvironment, and unfavorable patient prognosis. By employing 3D bioprinted co-culture systems and mouse models, we showed that the knockdown or knockout of IL7R inhibits tumor progression and intraperitoneal dissemination. Mechanistically, IL7R signaling promotes the polarization of macrophages toward an immunosuppressive phenotype through the NF-κB/CXCL1 axis. This is supported by the upregulated expression of Arg1 and IL-10, as well as the downregulated expression of pro-inflammatory markers. These polarized macrophages further enhance tumor cell proliferation and invasion, thereby forming a tumor-immune feedback loop. In conclusion, this study clarifies how IL7R signaling mediates crosstalk between ovarian cancer cells and macrophages to maintain the homeostasis of the immunosuppressive tumor microenvironment (TME).

FSP1 inhibition enhances olaparib sensitivity in BRCA-proficient ovarian cancer patients via a nonferroptosis mechanism

AbstractPoly ADP-ribose polymerase inhibitors (PARPis) exhibit promising efficacy in patients with BRCA mutations or homologous repair deficiency (HRD) in ovarian cancer (OC). However, less than 40% of patients have HRD, it is vital to expand the indications for PARPis in BRCA-proficient patients. Ferroptosis suppressor protein 1 (FSP1) is a key protein in a newly identified ferroptosis-protective mechanism that occurs in parallel with the GPX4-mediated pathway and is associated with chemoresistance in several cancers. Herein, FSP1 is reported to be negatively correlated with the prognosis in OC patients. Combination therapy comprising olaparib and iFSP1 (a FSP1 inhibitor) strongly inhibited tumour proliferation in BRCA-proficient OC cell lines, patient-derived organoids (PDOs) and xenograft mouse models. Surprisingly, the synergistic killing effect could not be reversed by ferroptosis inhibitors, indicating that mechanisms other than ferroptosis were responsible for the synergistic lethality. In addition, cotreatment was shown to induce increased γH2A.X foci and to impair nonhomologous end joining (NHEJ) activity to a greater extent than did any single drug. Mass spectrometry and immunoprecipitation analyses revealed that FSP1 interacted with Ku70, a classical component recruited to and occupying the end of double-strand breaks (DSBs) in the NHEJ process. FSP1 inhibition decreased Ku70 PARylation, impaired subsequent DNA-PKcs recruitment to the Ku complex at DSB sites and was rescued by restoring PARylation. These findings unprecedentedly reveal a novel role of FSP1 in DNA damage repair and provide new insights into how to sensitize OC patients to PARPi treatment.

Identification of Vesicle‐Mediated Transport‐Related Genes for Predicting Prognosis, Immunotherapy Response, and Drug Screening in Cervical Cancer

ABSTRACT Background Cervical cancer is one of the most common malignancies among women. Vesicle‐mediated transport mechanisms significantly influence tumor cell behavior through intercellular material exchange. However, prognostic significance in CC patients remains underexplored. Research Design and Methods We identified differentially expressed vesicle‐mediated transport‐related genes from TCGA and GeneCards datasets through differential expression analysis. We constructed a prognostic model using Cox regression and LASSO regression, categorized patients into high‐ and low‐risk groups, and validated the model in the GEO data set. A nomogram integrating clinical features and risk scores demonstrated the model's independent prognostic capability. We analyzed tumor immune cell infiltration, immune checkpoints, and predicted immunotherapy responses in the high‐ and low‐risk groups. Finally, we screened potential drugs for targeting CC and conducted drug‐sensitivity analysis. Results We successfully established a 10‐gene prognostic model based on VMTRGs. The low‐risk group exhibited favorable prognosis, significant immune cell infiltration, and promising immunotherapy response, whereas the high‐risk group showed higher sensitivity to chemotherapeutic agents such as Docetaxel and Paclitaxel. Potential drugs identified for targeting CC patients included Megestrol acetate, Lenvatinib, Adavosertib, and Barasertib. Conclusions The VMTRG‐based prognostic model demonstrates reliable clinical prognostic value and enhances understanding of vesicle‐mediated transport mechanisms in CC.

Multiomics profiling and experiments in preclinical models revealed RAD51-IN-1 as a synergistic potentiator of anlotinib sensitivity

Anlotinib has demonstrated preliminary efficacy as a first-line maintenance therapy for ovarian cancer. However, clinical responses vary widely. To investigate resistance mechanisms and explore rational combinations, pretreatment tumors from 18 patients in clinical trial NCT04807166 underwent whole-exome and RNA sequencing and stratified into sensitive and resistant groups based on progression-free survival. VEGFR-related mutations were enriched in sensitive tumors, whereas resistant tumors showed increased activity of DNA repair pathways and Notch signaling. In vitro screening identified strong synergy between anlotinib and the RAD51 inhibitor RAD51-IN-1, which outperformed the Notch inhibitor FLI-06 in resistant patient-derived organoids. Mechanistic studies revealed that RAD51 inhibition was associated with impaired HRR and increased sensitivity to anlotinib. In vivo, combined treatment with anlotinib and RAD51-IN-1 significantly reduced tumor burden without notable toxicity. These findings suggest that RAD51-mediated HRR may contribute to anlotinib resistance and support RAD51 inhibition as a promising approach to overcome therapeutic resistance in ovarian cancer.