Biology subjects

Buchanan, L.

Publications and source records attributed to Buchanan, L..

3 recordsLinked to original sources

bioRxiv2026

The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres

Cancers maintain their telomeres through two telomere maintenance mechanisms: 85-90% of cancers rely on telomerase (TEL+), while 10-15% of cancers adopt the Alternative Lengthening of Telomeres (ALT) pathway. The Break-Induced Replication (BIR) pathway plays a critical role in maintaining telomere length in the ALT+ cells. In both yeast and human, PIF1, a 5' to 3' helicase, is required for the robust activity of BIR. However, the extent of human PIF1 (hPIF1) involvement in the ALT pathway remains unknown. Here we showed that hPIF1 can be recruited to damaged telomeres in ALT+ cells. In addition, we demonstrated that inhibition of hPIF1 induced DNA damage and G quadruplex (G4) accumulation at ALT telomeres, leading to a moderate reduction of the mean telomere length. Most interestingly, we demonstrated that inhibition of hPIF1 also attenuates checkpoint activation, BLM recruitment, single-stranded DNA (ssDNA) formation, DNA damage, and G4s at telomeres in the FANCM deficient ALT+ cells. Finally, we showed that inactivation of hPIF1 affects the viability of both ALT+ and TEL+ cancers, suggesting that hPIF1 is a potential drug target for cancer therapy.

molecular biology↗

bioRxiv2026

Integrated Patient-Derived Xenograft and Patient-Derived Cell Models Reveal Therapeutic Vulnerabilities Beyond Standard-of-Care Therapy in Endometrial Cancer

Endometrial cancer (EC), the most common gynecologic malignancy in the USA, has seen limited improvement in patient outcomes over recent decades, underscoring the need for relevant preclinical models. To address EC heterogeneity, we established an integrated platform of patient-derived xenografts (PDXs) and matched patient-derived primary cancer cells (PDCs) for disease modeling and systematic drug sensitivity testing. Fresh tumor specimens (n=103) were collected from EC patients to generate PDXs in immunodeficient mice and corresponding PDCs. Fifty-three PDX models were successfully established (52% engraftment rate), with higher success observed in high-grade, recurrent, metastatic tumors (70%), compared with their low-grade counterparts (56%). Histopathologic and immunohistochemical analyses confirmed that PDX tumors faithfully preserved morphology, hormone receptor status, and intertumoral heterogeneity across multiple passages. Using 13 PDC models, we performed an unbiased screening of 179 FDA-approved oncology drugs, revealing marked intertumoral variability in drug response. Almost all PDC models exhibited limited sensitivity to NCCN-recommended therapies, highlighting the need for alternative treatment strategies. In contrast, multiple FDA-approved agents including epigenetic modulators, dual PI3-kinase/HDAC inhibitors, topoisomerase II inhibitors, and proteasome inhibitors demonstrated potent antitumor activity. Importantly, a low-dose combination of the DNA methyltransferase inhibitor 5-azacytidine and the histone deacetylase inhibitor romidepsin significantly suppressed tumor growth across six independent PDX models. Together, these findings establish a comprehensive PDX and PDC platform as a robust translational resource. By capturing the histopathologic and molecular diversity of EC and identifying clinically actionable therapeutic advantages, including an epigenetic combination regimen, this study offers a translational resource for preclinical drug evaluation.

cancer biology↗

bioRxiv2023

Incorporating Radiopacity into Implantable Polymeric Biomedical Devices for Clinical Radiological Monitoring

Longitudinal radiological monitoring of biomedical devices is increasingly important, driven by risk of device failure following implantation. Polymeric devices are poorly visualized with clinical imaging, hampering efforts to use diagnostic imaging to predict failure and enable intervention. Introducing nanoparticle contrast agents into polymers is a potential method for creating radiopaque materials that can be monitored via computed tomography. However, properties of composites may be altered with nanoparticle addition, jeopardizing device functionality. This, we investigated material and biomechanical response of model nanoparticle-doped biomedical devices (phantoms), created from 0-40wt% TaOx nanoparticles in polycaprolactone, poly(lactide-co-glycolide) 85:15 and 50:50, representing non-, slow and fast degrading systems, respectively. Phantoms degraded over 20 weeks in vitro, in simulated physiological environments: healthy tissue (pH 7.4), inflammation (pH 6.5), and lysosomal conditions (pH 5.5), while radiopacity, structural stability, mechanical strength and mass loss were monitored. The polymer matrix determined overall degradation kinetics, which increased with lower pH and higher TaOx content. Importantly, all radiopaque phantoms could be monitored for a full 20-weeks. Phantoms implanted in vivo and serially imaged, demonstrated similar results. An optimal range of 5-20wt% TaOx nanoparticles balanced radiopacity requirements with implant properties, facilitating next-generation biomedical devices.

bioengineering↗