Biology subjects

Zuiverloon, T. C. M.

Publications and source records attributed to Zuiverloon, T. C. M..

3 recordsLinked to original sources

bioRxiv2026

Stromal innervation is prognostic in non-muscle-invasive bladder cancer and predicted by a distinct microenvironmental transcriptomic signature

Peripheral nerves are increasingly recognized as active components of the tumor microenvironment (TME). Yet, their role in non-muscle-invasive bladder cancer (NMIBC) and response to Bacillus Calmette-Guerin (BCG) remains poorly defined. Using multispectral imaging, we characterized autonomic and sensory nerve populations within the tumor-adjacent stroma of 241 treatment-naive high-risk NMIBC tumor regions from 141 patients. Stromal tumor-associated nerve (STaN) abundance varied substantially across patients and was associated with aggressive clinicopathological features, BCG failure, and disease progression. Unsupervised clustering resolved distinct STaN phenotypic groups with differential clinical and spatial associations. Noradrenergic and a neurochemically heterogeneous STaN populations showed the strongest associations with adverse outcomes. In contrast, a mixed population of nerves with high expression of the synaptic vesicle protein synaptophysin exhibited prominent spatial remodeling associated with BCG failure, despite limited prognostic value by abundance alone. Integration with an independent single-cell atlas nominated cancer-associated fibroblasts and mast cells as candidate cellular intermediaries of neural communication within the TME. Matched transcriptomic profiling revealed coordinated neuronal, extracellular matrix, lipid metabolism, and immune programs in STaN-high tumors, whereas STaN-low tumors preferentially enriched proliferative and hypoxic stress-response pathways. Leveraging these transcriptional features, we developed a transcriptomic classifier that distinguished STaN-high from STaN-low tumors in an independent test cohort (AUC = 0.87) and stratified clinical outcomes in additional patient cohorts. Together, these findings establish tumor innervation as a heterogeneous and clinically relevant feature of the NMIBC microenvironment, with neural abundance, phenotype, and spatial organization capturing distinct aspects of tumor behavior and clinical outcome.

cancer biology↗

bioRxiv2024

Integrative analysis of patient-derived tumoroids and ex vivo organoid modeling of ARID1A loss in bladder cancer reveals therapeutic molecular targets

Somatic mutations in ARID1A (AT-rich interactive domain-containing protein 1A) are present in approximately 25% of bladder cancers (BC) and are associated with poor prognosis. With a view to discover effective treatment options for ARID1A-deficient BC patients, we set out to identify targetable effectors dysregulated consequent to ARID1A deficiency. Integrative analyses of ARID1A depletion in normal organoids and data mining in publicly available datasets revealed upregulation of DNA repair and cell cycle-associated genes consequent to loss of ARID1A and identified CHEK1 (Checkpoint kinase 1) and chromosomal passenger complex member BIRC5 (Baculoviral IAP Repeat Containing 5) as therapeutically drug-able candidate molecular effectors. Ex vivo treatment of patient-derived BC tumoroids with clinically advanced small molecule inhibitors targeting CHEK1 or BIRC5 was associated with increased DNA damage signalling and apoptosis, and selectively induced cell death in tumoroids lacking ARID1A protein expression. Thus, integrating public datasets with patient-derived organoid modelling and ex-vivo drug testing can uncover key molecular effectors and mechanisms of oncogenic transformation, potentially leading to novel therapeutic strategies. Our data point to ARID1A protein expression as a suitable candidate biomarker for the selection of BC patients responsive to therapies targeting BIRC5 and CHEK1.

cancer biology↗

bioRxiv2022

Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

Bacillus Calmette-Guerin (BCG) is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity. Here, we found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1{beta} after heterologous ex-vivo stimulation of circulating monocytes 6- 12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40- 1.01)) for respiratory infections in BCG-treated versus non-BCG-treated NMIBC patients. An epigenomics approach combining ChIP-sequencing and RNA-sequencing with in-vitro trained immunity experiments identified enhanced inflammasome activity in BCG-treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC, suggesting a link between trained immunity and oncological outcome.

immunology↗