Biology subjects

Moyer, J.

Publications and source records attributed to Moyer, J..

6 recordsLinked to original sources

bioRxiv2026

CMTM6-Silencing Microbial Immunotherapy Reprograms PDAC Tumors and Restores T-cell Function

Despite recent advances in immunotherapy for advanced malignancies, Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to current immunotherapy due to dense fibrosis, limited antigen presentation, and myeloid-driven immune suppression. Here we report the tumor-targeting, immune remodeling, and safety profiles of the attenuated Salmonella enterica serovar Typhimurium strain CRC2631, and of iSTORM, a next-generation derivative engineered for tumor-localized CMTM6 silencing. CRC2631 preferentially colonizes orthotopic and genetically engineered PDAC tumors, with enrichment in primary lesions and metastases. Tumor-localized CRC2631 induces chemokine and adhesion programs consistent with leukocyte recruitment, increases intratumoral activated T-cell fractions, and triggers transcriptional signatures aligned with innate sensing, interferon signaling, antigen-processing and presentation, and apoptosis programs. iSTORM extends this platform by delivering CMTM6-targeting shRNA to modulate a PD-L1-stabilizing, myeloid-associated immune-evasion programs within tumor-colonized tissue. Compared with CRC2631, iSTORM increases intratumoral CD8+ T cells, shifts T-cell state toward activation with reduced exhaustion-prone features, strengthens antigen-presentation programs, and achieves deeper tumor control. A lyophilized formulation preserves immune remodeling while improving deployability. Mechanistically, glycan arrays and functional studies support mannose-rich glycan-guided tumor engagement. iSTORM toxicity studies, including systemic cytokine, hematologic, blood chemistry, and lethality demonstrate a favorable safety profile. Collectively, these findings establish iSTORM as a safe, programmable, CMTM6-silencing microbial immunotherapy platform that selectively targets and penetrate PDAC tumors to unleash anti-tumor immune activities. What is already known on this topicPDAC is highly resistant to immune checkpoint blockade because dense stroma and myeloid-dominated suppression prevent effective T-cell infiltration; attenuated Salmonella strains can selectively colonize tumors but first-generation agents showed limited efficacy and safety concerns. What this study addsThis study defines CRC2631/iSTORM as a tumor-selective microbial immunotherapy that exploits surface-exposed, mannose-rich N-glycans to colonize PDAC, delivers CMTM6 silencing, and restores CD8+ T-cell activation and tumor control in models resistant to PD-1 blockade immunotherapy. How this study might affect research, practice or policyThese findings provide a mechanistic blueprint for glycan-guided, CMTM6-targeted bacterial "living drugs," support rational combination strategies for deepening therapeutic effect, and establish a lyophilized, biocontained platform that could be developed into scalable microbial immunotherapies for PDAC and other immunologically cold solid tumors.

cancer biology↗

bioRxiv2025

Therapy-induced PSMA2 Sensitizes Prostate Cancer Cells to Residual Androgen and Promotes Neuroendocrine Lineage Transformation

Aberrant activation of the androgen receptor (AR) pathway drives prostate cancer (PCa). Androgen deprivation therapy (ADT) and next-generation AR blockade (e.g., enzalutamide) are initially effective, but virtually all patients develop castration-resistant prostate cancer (CRPC), which frequently transitions to treatment-emergent neuroendocrine PCa (tNEPC) following AR suppression. The molecular logic that links AR blockade to lineage plasticity remains incompletely understood. Here, we identify PSMA2 (Proteasome Subunit Alpha 2) as a treatment-induced effector that mechanistically connects AR blockade to tNEPC evolution. Enzalutamide induces PSMA2 expression in AR-expressing PCa cells. Enforced PSMA2 expression accelerates HSP90 turnover, hypersensitizes AR to residual post-castration androgen, drives AR nuclear activity under androgen-poor conditions, and confers enzalutamide resistance. Conversely, PSMA2 silencing stabilizes HSP90, desensitizes CRPC to androgen, and re-sensitizes resistant cells to enzalutamide-induced cell death. Importantly, PSMA2 also promotes lineage plasticity: treatment-induced PSMA2 enhances transcriptional and phenotypic conversion toward tNEPC. Thus, we uncover a single stress-induced node (PSMA2) that both maintains AR-dependent survival under ADT and fuels the neuroendocrine transition. PSMA2 marks an AR-hypersensitized transitional state and is itself a therapeutically actionable driver of tNEPC evolution, revealing an opportunity for rational interception of the lethal ADT-CRPC-tNEPC trajectory.

cancer biology↗

bioRxiv2025

Pan-Cancer PDOs Preserve Tumor Heterogeneity and Uncover Therapeutic Vulnerabilities

We developed a tumor-matched, pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 190 patients across 15 cancer types to advance functional precision oncology. Our comprehensively characterized PDOs showed 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation with parent tumors. Gene expression in PDOs remained stable across [≥] 10 passages, supporting reproducibility for long-term drug screening. Even PDOs with low genomic concordance retained oncogenic drivers, supporting their use as disease models. Clonality analysis revealed that 85% of PDOs preserved dominant tumor clones. Higher genomic concordance was associated with greater clonal similarity, while lower genomic concordance was associated with clonal divergence. Functional assays showed that 58% of PDOs from a subset of patients ineligible for FDA-approved PARP inhibitors responded to Talazoparib, with sensitivity linked to alterations in DNA damage repair. Combination screens revealed drugs that effectively overcame resistance, especially in TP53-mutant PDOs. In summary, our platform supports investigation of targeted therapies, identification of molecular features linked to drug sensitivity, and translational discovery, offering insights into personalized cancer treatment beyond current biomarker guidelines.

cancer biology↗

bioRxiv2023

Novel co-culture strategies of tumor organoids with autologous T-cells reveal clinically relevant combinations of immune-checkpoint and targeted therapies

Patient derived tumor organoids (PDTOs) have become relevant pre-clinical models for therapeutic modelling since they highly recapitulate patients response to treatment. Nevertheless, their value for immunotherapy modelling has not been fully explored. We developed a tumor processing protocol that enable the establishment of PDTOs and tumor infiltrating lymphocytes (TILs) isolation. By the optimization of functional assays, we compared the T-cells effector functions of matching PBMCs and TILs, demonstrating that PBMCs after co-culture and TILs after initial expansion display similar responses. In addition, the evaluation of cytokine production by fluorospot in combination with an image-based killing assay enable the screening of different immune-checkpoint inhibitors as well as its combination with target inhibitors. Our proof-of-concept functional assays showed the potential and versatility of PDTOs and T-cells co-culture systems for immunotherapy screening. The optimization of scalable functional assays downstream co-culture represents a significant step forward to increase the value of PDTOs as pre-clinical models for immunotherapeutic screens.

immunology↗

bioRxiv2023

The Interplay between Mutagenesis and Extrachromosomal DNA Shapes Urothelial Cancer Evolution

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity. In this study, we investigate the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants. We superimposed mutational signatures and phylogenetic analyses of matched serial tumors from patients with urothelial cancer to define the evolutionary patterns of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas mutational bursts comprising hundreds of late subclonal mutations are induced by chemotherapy. Using a novel genome graph computational paradigm, we observed frequent circular high copy-number amplicons characteristic of extrachromosomal DNA (ecDNA) involving double-minutes, breakage-fusion-bridge, and tyfonas events. We characterized the distinct temporal patterns of APOBEC3 mutations and chemotherapy-induced mutations within ecDNA, gaining new insights into the timing of these events relative to ecDNA biogenesis. Finally, we discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA amplicons. These CCND1 ecDNA amplification events persisted and increased in complexity incorporating additional DNA segments potentially contributing selective fitness advantage to the evolution of treatment resistance. Our findings define fundamental mechanisms driving urothelial cancer evolution and have therapeutic implications for treating this disease.

genomics↗

bioRxiv2022

A Rigid Parallel-Plate Artificial Placenta Oxygenator with a Hemocompatible Blood Flow Path

Extremely preterm infants have poor clinical outcomes due to lung immaturity. An artificial placenta could provide extracorporeal gas exchange, allowing normal lung growth outside of the uterus, thus improving outcomes. However, current devices in development use hollow-fiber membrane oxygenators, which have a high rate of bleeding and clotting complications. Here, we present a novel style of oxygenator composed of a stacked array of rigid and flat silicon semi-permeable membranes. Using computational fluid dynamic (CFD) modeling, we demonstrated favorable hemocompatibility properties, including laminar blood flow, low pressure drop, and minimal cumulative shear stress. We then constructed and tested prototype devices on the benchtop and in an extracorporeal pig model. At 20 mL/min of blood flow, the oxygenators exhibited an average oxygen flux of 0.081 {+/-} 0.020 mL (mean {+/-} standard error) and a pressure drop of 2.25 {+/-} 0.25 mmHg. This study demonstrates the feasibility of a building a stacked flat-plate oxygenator with a blood flow path informed by CFD.

bioengineering↗