Biology subjects

Wang, Q.-E.

Publications and source records attributed to Wang, Q.-E..

4 recordsLinked to original sources

bioRxiv2026

STN1 upregulation promotes PARPi resistance in BRCA2-deficient cancer cells via replication fork protection and suppression of ssDNA gap formation

PARPi are effective therapy for BRCA1/2 mutant cancers, yet recurrent PARPi resistance frequently develops. The underlying mechanism of PARPi resistance remains largely unresolved. Here, we identify STN1, a component of the CTC1/STN1/TEN1 (CST) complex, as a modulator of PARPi resistance in BRCA2-deficient cells. RNA-seq analysis of PARPi-resistant cancer cells from BRCA2-mutated backgrounds shows largely distinct transcriptomic profiles with limited overlap, suggesting multiple routes to resistance. Notably, STN1 is consistently upregulated in resistant cells. We observe that overexpression of STN1 enhances Olaparib resistance in multiple BRCA2-deficient cell lines and alleviates DNA damage under replication stress. Mechanistically, we find that STN1 overexpression increases RAD51 loading to stalled replication forks while restricting MRE11 recruitment in BRCA2-deficient cells, thereby protecting stalled forks from nascent-strand degradation. Furthermore, STN1 overexpression rescues the accumulation of ssDNA gaps, a major determinant of PARPi sensitivity in BRCA2-deficient cells. Taken together, these findings suggest that elevated STN1 levels can partially compensate for BRCA2 loss by stabilizing stalled replication forks and limiting ssDNA gap accumulation. Our study uncovers a STN1-dependent pathway of replication stress tolerance that promotes PARPi resistance independently of homologous recombination restoration, highlighting STN1 as a potential biomarker and mechanistic contributor to therapeutic resistance in BRCA2-mutated cancers.

cancer biology↗

bioRxiv2026

Intracellular Delivery of Peptides and Proteins with an Engineered Membrane Translocation Domain

Antibodies and other protein therapeutics have revolutionized medicine, but their application is largely limited to extracellular targets. The lack of efficient intracellular delivery methods remains a major bottleneck. Here, we engineered a family of small ([~]90 amino acids), metabolically stable membrane translocation domains (MTDs) by modifying the loop sequences of a human fibronectin type III (FN3) domain. The most potent variant, MTD4, is highly cell-permeable and can be recombinantly fused to the N- or C-terminus of any peptide or protein, serving as a versatile "plug-and-play" vehicle. We demonstrate that MTD4 fusions efficiently deliver a wide variety of functional peptides and proteins into the cytosol and nucleus of eukaryotic cells, both in vitro and in vivo. Following systemic administration, MTD4 fusion proteins exhibit broad biodistribution and homogenous tissue penetration in mice. Importantly, MTD4 is effective at low nanomolar (nM) concentrations, making it a promising platform for addressing a vast range of intracellular and previously "undruggable" targets.

bioengineering↗

bioRxiv2025

HO-3867 mediated modulation of Extracellular vesicles and Tumor microenvironment: A novel immunotherapeutic strategy for ovarian cancer

IntroductionOvarian cancer (OC) remains the most lethal gynecologic malignancy, with poor long-term survival, largely due to its diagnosis at advanced stages and its high rate of recurrence with resistance to platinum therapies. This study evaluates the therapeutic efficacy of HO-3867, a STAT3 inhibitor, and bevacizumab, an anti-VEGF antibody, alone and in combination in an immunocompetent (IC) syngeneic ovarian cancer progression model. MethodsThe ability of HO-3867 to induce macrophage polarization was assessed in RAW264.7 cells, while its impact on anti-tumor immunity was evaluated in splenocytes co-cultured with ID8 and OC ascites cells. Immune modulation, including cytokine induction, extracellular vesicle (EV) release, and endosomal sorting complex required for transport (ESCRT) protein expression, was analyzed in-vitro and using in-vivo OC model. The therapeutic effects of HO-3867 and bevacizumab were examined in vivo by measuring ascites volume, EV secretion levels, and immune cell populations via flow cytometry. ResultsOur results demonstrate that combination therapy significantly reduced ascites accumulation, and limited peritoneal disease spread in ovarian cancer mouse models. EV analysis revealed a decrease in total EVs and CD9+ subpopulations, which correlated with the associated ESCRT proteins involved in EV formation and secretion implicating EVs in tumor progression and immune modulation. Flow cytometry analysis of ascites immune cell populations showed that combination therapy reduced myeloid-derived suppressor cells (MDSCs) and their PD-L1 expression, while enhancing CD8+ T cell cytotoxicity via granzyme B secretion. Cytokine profiling revealed upregulation of IFN-{gamma} and downregulation of IL-6, IL-10 and CXCL-2 suggesting enhanced anti-tumor immune response. Furthermore, HO-3867 promoted macrophage polarization toward tumoricidal M1 phenotype and reduced MDSC expansion in-vitro, enhancing anti-tumor immunity. ConclusionHO-3867 and bevacizumab synergistically reprogram the tumor microenvironment, inhibit EV-mediated progression, and enhance antitumor immunity. These findings support its immunomodulatory potential in ovarian cancer ascites, offering a promising therapeutic strategy.

cancer biology↗

bioRxiv2025

XPC loss-of-function triggers melanomagenesis through CDKN2A downregulation

We identified a novel XPC variant, c.2420+5G>A (XPCvar), in siblings with multiple melanomas, inherited alongside c.779+1G>T, which results in an absent or disrupted protein. However, they did not exhibit significantly higher nucleotide excision repair (NER) deficits compared to their unaffected parents, suggesting an NER-independent tumor suppressor function for XPC. XPC knockdown increased cell proliferation and tumorigenicity in vitro without affecting NER. Single-cell RNA sequencing revealed lower Cdkn2a in Xpcvar/var mouse melanocytes. Additionally, XPC knockdown downregulated CDKN2A in vitro. Furthermore, patient fibroblasts showed decreased p16INK4a, which was rescued by XPC overexpression. ChIP-PCR and luciferase assays confirmed XPC binding to the CDKN2A promoter, initiating transcription. Premature stop codon read-through, with gentamicin, restored XPC and p16INK4A in patient fibroblasts. These suggest that XPC regulates CDKN2A and XPC loss might promote melanomagenesis by downregulating CDKN2A, independent of its NER function. We provide preclinical evidence for potential preventive and/or therapeutic strategies for similarly affected individuals. STATEMENT OF SIGNIFICANCECharacterizing a novel XPC variant identified in patients with melanoma revealed a non-canonical role for XPC in regulating CDKN2A transcription. XPC binding to the CDKN2A promoter is crucial for CDKN2A expression and might suppress melanomagenesis. This expands our understanding of melanomagenesis and suggests potential therapies targeting XPC-mediated regulation of CDKN2A.

cancer biology↗