Biology subjects

Boormans, J. L.

Publications and source records attributed to Boormans, J. L..

4 recordsLinked to original sources

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

T Cell-to-Stroma Enrichment (TSE) score: a gene expression metric that predicts response to immune checkpoint inhibitors in patients with urothelial cancer

Immune checkpoint inhibitors (ICIs) improve overall survival in patients with metastatic urothelial cancer (mUC). To identify predictive markers of response, whole-genome DNA (n=70) and RNA-sequencing (n=41) were performed using fresh metastatic biopsies prior to treatment with pembrolizumab. PD-L1 combined positivity score did not, whereas tumor mutational burden and APOBEC mutagenesis modestly predicted response. Using gene expression analysis, we defined the T cell-to-stroma enrichment (TSE) score, a signature-based metric that captures the relative abundance of T cells and stromal cells. Patients with a positive and negative TSE score show progression-free survival rates at 6 months of 67 and 0%, respectively. The TSE score was captured by immunofluorescence in tumor tissue, and validated in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS). In conclusion, the TSE score represents a clinically applicable marker that potentially aids in prospectively selecting patients with mUC for ICI treatment.

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↗

bioRxiv2021

Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma

BackgroundMolecular characterization of primary urothelial carcinoma (UC) revealed molecular subtypes with different genomic, transcriptomic, and clinicopathological characteristics, which might guide therapeutic decision making. A comprehensive molecular characterization of metastatic UC (mUC), however, is currently lacking in the literature. Because of the lethality of mUC, with few therapeutic options available for patients, a multi-omics characterization of mUC could aid to improve patient selection for new and existing therapies. MethodsTo define the molecular landscape of mUC and to identify potential targets for therapy, we performed whole genome DNA sequencing on fresh-frozen metastatic tumor biopsies of 116 mUC patients, and mRNA sequencing on 90 matched biopsies. ResultsHierarchical clustering based on mutational signatures revealed two major genomic subtypes. The most prevalent subtype (67%) consisted almost exclusively of tumors with high APOBEC mutagenesis. APOBEC mutagenesis was detected in 91% of the samples, and appeared to be an ongoing process in mUC based on analysis of eight patients from whom serial biopsies were obtained during treatment. Contrary to the overall distribution of mutations, APOBEC associated mutations occurred throughout the genome, and independently of predicted accessible or transcribed genomic regions, suggesting that these mutations were generated during replication. Transcriptomic analysis revealed five mRNA-based subtypes: two luminal subtypes (40%), a stroma-rich (24%), basal/squamous (23%), and non-specified subtype (12%). The transcriptomic subtypes were different regarding driver gene alterations (e.g. ELF3 and TSC1), gene amplifications (NECTIN4 and PPARG), pathway activity, and immune cell infiltration. By integrating the genomic and transcriptomic data, potential therapeutic options per transcriptomic subtype and individual patient were proposed. ConclusionsThis study expands our knowledge on the molecular landscape of mUC, and serves as a reference for subtype-oriented and patient-specific research on the etiology of mUC, and for novel drug development. Trial registrationThe mUC cohort studied here is part of the Netherlands nationwide study of the center for personalized cancer treatment consortium (CPCT-02 Biopsy Protocol, NCT01855477), and the Drug Rediscovery Protocol (DRUP Trial, NCT02925234).

cancer biology↗