Biology subjects

Prins, R. M.

Publications and source records attributed to Prins, R. M..

5 recordsLinked to original sources

bioRxiv2026

Predictable clonal hierarchies from restricted progenitors provide a framework for cell type-specific therapies in glioblastoma

Extensive molecular profiling has revealed profound heterogeneity in glioblastoma (GBM), yet how cellular lineages organize over time to govern tumor propagation and therapeutic response remains poorly understood. Existing single-cell approaches define transcriptional states but provide limited insight into how clonal dynamics shape functional tumor behavior. Here, we integrate high-complexity combinatorial DNA barcoding with single-cell transcriptomics in direct-from-patient IDH1-wild-type GBM, enabling lineage-resolved mapping of progenitor organization in a human microenvironmental context. Across 235,155 malignant cells from nine tumors, clonal relationships form reproducible lineage tracks in which distinct progenitor populations give rise to specific differentiated cell types, revealing that tumor growth is sustained by multiple non-redundant progenitors rather than a single dominant population. These progenitors exhibit distinct propensities for self-renewal, fate restriction, and cross-compartment interactions, collectively accounting for the full spectrum of tumor states. Using this lineage-resolved framework, we identify complementary drug targets in distinct progenitor compartments and demonstrate that hierarchy-informed combination therapies disrupt progenitor-progenitor interactions and reshape lineage output. These findings move beyond descriptive heterogeneity to define functional logic underlying GBM propagation and establish a generalizable framework for rational, cell type-specific combinatorial therapies.

cancer biology↗

bioRxiv2025

Systems analysis uncovers early temozolomide responses and peptide antigens in glioblastoma

Temozolomide (TMZ) is the standard treatment for nearly all glioblastoma (GBM) patients, as it is the only chemotherapy shown to extend overall survival. However, this benefit is limited to a few months, underscoring the need for combination strategies to improve its efficacy. While TMZ-induced DNA damage can both mediate cytotoxicity and promote resistance, DNA damage more broadly can also stimulate immune activation. To evaluate its immunomodulatory potential, we characterized the previously unexplored early, cell-intrinsic consequences of TMZ in GBM cells, spanning DNA damage, stress responses, and antigen presentation. A multi-omics approach combining RNA sequencing and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) profiled changes in gene expression, nascent protein translation, steady-state protein levels, kinase-substrate phosphorylation patterns, and MHC-I peptide presentation in GBM cells within 72 hours of TMZ exposure. This analysis revealed rapid activation of DNA damage signaling and p53-associated stress pathways, alongside dynamic changes in protein synthesis and antigen presentation. A set of TMZ treatment-associated peptide antigens (TAPAs) was identified, including peptides derived from stress response proteins, phosphorylated MHC-I peptides, and those induced by other genotoxic treatments such as radiation. Several of these peptides were also detected in recurrent GBM patient tumors. Our findings suggest that TMZ not only triggers early adaptive and potentially resistance-associated stress programs but may also enhance the immune visibility of GBM cells. These data highlight potential windows for combination therapies with TMZ that bolster immune recognition of GBM, while the systems approach provides a framework to examine how genotoxic therapies across cancers alter tumor immunogenicity.

cancer biology↗

bioRxiv2025

A Human Tumor-Immune Organoid Model of Glioblastoma

A major obstacle to identifying effective therapies for the aggressive brain tumor glioblastoma is the lack of human-specific, immunocompetent models that reflect the human tumor microenvironment. To address this, we developed the immune-Human Organoid Tumor Transplantation (iHOTT) model. This is an autologous co-culture platform that integrates patient-derived tumor cells and matched peripheral blood mononuclear cells (PBMCs) within human cortical organoids, enabling the study of the patient-specific immune response to the tumor and tumor-immune interactions. This platform preserves tumor and immune populations, immune signaling, and cell-cell interactions observed in patient tumors. Treatment of iHOTT with pembrolizumab, a checkpoint inhibitor, mirrored cell type shifts and cell interactions observed in patients. TCR sequencing further revealed pembrolizumab-driven expansion of stem-like CD4-T-cell clonotypes exhibiting patient-specific repertoires. These findings establish iHOTT as a physiologically relevant platform for exploring autologous tumor-immune interactions and underscore the critical need for antigen-targeted strategies to enhance immunotherapy in glioblastoma.

cancer biology↗

bioRxiv2022

Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.

The mechanism by which ICI (immune checkpoint inhibitor) induce durable antitumor T cell activity remains inadequately defined. Tumors from melanoma patients who responded to ICI or MAPK pathway inhibitors (MAPKi) therapy generally displayed increased T cell infiltration and interferon gamma (IFN{gamma}) pathway activation. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi. Comparing the transcriptome of cohorts of melanoma patients treated with ICI or MAPKi therapy, we discovered that response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with higher clonal diversity than MAPKi. Higher B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in robust increases of IFN{gamma} pathway activity and CXCL13 expression in tumor reactive CD8 T cells after ICI therapy. Accordingly, ICI-treated melanoma patients, but not MAPKi, whose tumors displayed higher BCR diversity and IFN{gamma} pathway score, survived significantly longer than those with either one or none. Thus, response to ICI, but not to MAPKi therapy, induces the recruitment of clonally diverse antigen presenting B cells that activate tumor specific, cytotoxic CD8 T cells to effect a durable antitumor immune response. Our result suggests that enhancing B cells tumor antigen presentation to intratumoral CD8 T cells can increase the rate of long-term response to ICI therapy.

cancer biology↗

bioRxiv2019

IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

Aberrant alternative splicing (AS) is widespread in cancer, leading to an extensive but largely unexploited repertoire of potential immunotherapy targets. Here we describe IRIS, a computational platform leveraging large-scale cancer and normal transcriptomics data to discover AS-derived tumor antigens for T-cell receptor (TCR) and chimeric antigen receptor T-cell (CAR-T) therapies. Applying IRIS to RNA-Seq data from 22 glioblastomas resected from patients, we identified candidate epitopes and validated their recognition by patient T cells, demonstrating IRISs utility for expanding targeted cancer immunotherapy.

bioinformatics↗