Biology subjects

Berchem, G.

Publications and source records attributed to Berchem, G..

5 recordsLinked to original sources

bioRxiv2026

ACB1801 enhances tumor immunogenicity by targeting glycolysis/ferroptosis vulnerability and activating STAT1-signaling to overcome anti-PD-1 resistance in MSS colorectal cancer

BackgroundImmune checkpoint blockade (ICB) therapies demonstrate low efficacy in microsatellite stable (MSS) colorectal cancer (CRC) due to an immune-desert tumor microenvironment (TME) characterized by low antigen presentation and limited tumor-infiltrating lymphocytes (TILs). Harmine, a natural small-molecule and its promising derivatives ACB1801 have shown anti-tumor potential in preclinical models; however, their potential to reprogram the TME and overcome ICB resistance in MSS CRC remains unexplored. This study investigates whether and how ACB1801 can reshape TME to sensitize MSS CRC to ICB therapies. MethodsWe used the CT26 MSS colorectal cancer mouse model to evaluate the ability of the harmine derivative ACB1801 to enhance the efficacy of anti-PD-1 therapy. To characterize its mode of action, we performed immune landscape analysis and transcriptomic profiling of both CD45- and CD45+ tumor-derived cells. In parallel, mechanistic studies were conducted in vitro using mouse and human MSS CRC cell lines. ResultsWe demonstrate that the harmine derivative ACB1801 enhances the effectiveness of anti-PD-1 therapy in an MSS CRC mouse model. Combination therapy significantly increased CD8+ T cell infiltration and reduced regulatory T-cell (Treg) density in the TME. Transcriptomic profiling of CRC cells isolated from tumors treated with either anti-PD-1 alone or in combination with ACB1801 revealed significant enrichment of metabolic pathways in the combination group, characterized by reduced glycolysis and enhanced ferroptosis signatures. These findings were supported by in vitro data showing that ACB1801 reduces tumor cell glycolytic activity and promotes ferroptotic vulnerability. Mechanistically, ACB1801 induced STAT1 signaling, promoted CXCL10 release, and enhanced major histocompatibility complex class I (MHC-I)-dependent antigen presentation on tumor cells, thereby increasing tumor susceptibility to anti-PD-1 therapy. ConclusionCollectively, our findings indicate that combination therapy with harmine derivatives and ICBs represents a promising strategy for treating MSS CRC patients.

cancer biology↗

bioRxiv2026

Circulating immune profiling reveals impaired monocyte states and trajectories driving immunosuppression in glioblastoma

Glioblastoma (GBM) is an aggressive and lethal brain tumor marked by profound local and systemic immune dysfunction. Yet, the diagnostic and therapeutic relevance of peripheral impairments remains undefined. To clinically dissect their underlying mechanisms and pathological implications, we combined mass and flow cytometry with single-cell RNA-sequencing of peripheral blood mononuclear cells from GBM patients and healthy donors. GBM blood profiles were characterized by heterogeneous changes in classical monocytes, encompassing expanded, reduced and unchanged subsets, presenting distinct functional states, including antigen-presenting, interferon and metabolic subsets. Additional adaptations included myeloid-derived suppressor cell (MDSC) expansion and loss of non-classical monocytes. Trajectory analyses positioned MDSCs as an intermediate state, in continuum with the metabolic subset. Single-cell RNA-sequencing further showed antigen-presenting monocyte propensity to differentiate into tumor-associated macrophages. Circulating monocytes shared a "GBM-classical monocytic signature" exhibiting low MHC class II expression, altered cell-cell communication and increased anti-inflammatory mediators, such as IL1R2 and CD163. Lastly, lymphocyte alterations included decreased proportions of CD4+ T, natural killer (NK) and CD56+ T cells, retaining relatively conserved activation profiles, exemplified by up-regulation of alarmins S100A8/S100A9. These findings map systemic immune reprogramming in GBM, suggesting new avenues for non-invasive biomarker discovery and therapeutic strategies to restore anti-tumor immunity.

cancer biology↗

bioRxiv2025

Integrative multi-omics combined with functional pharmacological profiling in patient-derived organoids identifies personalized therapeutic vulnerabilities of adult high-grade gliomas

BackgroundPrecision medicine has transformed cancer treatment by tailoring therapies to specific molecular aberrations. Integrating high-resolution multi-omics with high-throughput functional profiling in patient-derived organoids of-fers a powerful strategy to further refine patient stratification. While (epi)genetic profiling has drastically improved the classification in diffuse adult gliomas, these advances have not yet translated into effective therapeutic interventions and precision medicine approaches remain to be established. Material and MethodsWe investigated a panel of 48 patient-derived organoid and orthotopic xenograft models of adult high-grade gliomas, comprehensively characterized at genomic, epigenomic and transcriptomic levels. A functional drug screen was performed on 27 organoid models using a 202-compound library targeting cancer-related pathways and epigenetic regulators. Unsupervised multi-omics factor analysis was employed to identify patient-specific therapeutic vulnerabilities. Validation included dose-dependent drug efficacy assessments, as well as biomarker assessment in patient tumors across molecular subgroups. ResultsMulti-omics analysis revealed a broad spectrum of molecular profiles capturing the genetic, epigenetic, and transcriptomic diversity of high-grade gliomas. Multi-omics factor analysis, integrating multi-omics and drug response profiles, identified distinct subgroups associated with IDH1 mutation and MYCN amplification. IDH1 mutant grade 4 astrocytomas showed selective sensitivity to histone deacetylase 3 inhibitors, while a MYCN-amplified glioblastoma responded preferentially to histone methyltransferase inhibitors. The differential drug responses were linked to specific (epi)genetic and transcriptomic biomarkers. While other glioblastomas exhibited heterogeneous treatment responses, no robust biomarker-defined responder subgroups were identified. ConclusionOur findings highlight the value of integrating multi-omics and functional profiling to inform precision medicine strategies. This approach enables the stratification of distinct patient subgroups in preclinical models, paving the way for tailored therapeutic interventions. While we observed distinct pharmacogenomic profiles in IDH1 mutant grade 4 astrocytomas and a MYCN-amplified glioblastoma, implementing precision medicine in other glioblastoma subtypes remains a substantial challenge. Key pointsO_LIIntegrating drug screening in a panel of patient-derived organoids with multi-omics enables pharmacogenomic profiling in adult diffuse high-grade gliomas C_LIO_LIIDH1 mutant grade 4 astrocytomas are sensitive to histone deacetylase 3 inhibitors C_LIO_LIMYCN-amplified glioblastoma exhibits distinct DNA methylation pattern and drug responses C_LI Study importanceTo date, attempts to develop effective precision medicine in adult high-grade gliomas failed. Here, we provide a preclinical framework for identifying personalized therapeutic by integrating multi-omics profiling with functional drug screening in patient-derived organoids. We show that IDH1 mutant high-grade astrocytomas present distinct therapeutic vulnerabilities compared to glioblastomas, linked to sensitivity to histone deacetylase 3 inhibitors. Within glioblastomas, we identified a distinct MYCN-amplified tumor, sensitive to histone methyltransferase inhibitors. Applying pharmacogenomic approaches using novel drug libraries holds promise for uncovering additional clinically relevant patient subgroups in the future. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/675145v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@12c04f9org.highwire.dtl.DTLVardef@fa8872org.highwire.dtl.DTLVardef@141de6org.highwire.dtl.DTLVardef@b72086_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Targeting the Atypical Chemokine Receptor 2 (ACKR2) improves the benefit of anti-PD-1 immunotherapy in melanoma

Immune checkpoint blockade (ICB) therapies, targeting PD-1 or PD-L1, have transformed cancer treatment, particularly for aggressive cancers. However, many patients fail to benefit from ICBs due to tumor characteristics, including a non-inflammatory tumor microenvironment (TME) that impedes immune cell infiltration. This study investigated the potential of targeting the Atypical Chemokine Receptor 2 (ACKR2), known for scavenging CXCR3-related chemokines crucial for lymphocyte recruitment to tumors. Genetic targeting of ACKR2 in melanoma cells increased the release of essential chemokines associated with the inflamed TME. In mouse models, ACKR2 inhibition suppressed tumor growth, improved survival, and enhanced activated immune cell infiltration into the TME. Moreover, ACKR2 targeting synergized with anti-PD-1 therapy, overcoming resistance to anti-PD-1 and improving its efficacy. Analysis of melanoma patient data from The Cancer Genome Atlas (TCGA) revealed that patients with high levels of chemokines scavenged by ACKR2 had significantly better survival rates, with increased expression of NK cell and CD8 T cell markers indicating their presence in the TME. Notably, even in patients with high CD8 expression, those expressing low ACKR2 survived better than those expressing high ACKR2. This study emphasizes the clinical importance of targeting ACKR2 as an attractive strategy for the development of combination immunotherapies to treat cold tumors, which are clinically stratified to not be eligible for ICB-based therapy.

cancer biology↗

bioRxiv2023

Glioblastoma-instructed microglia transit to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

BackgroundA major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials. MethodsHere, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA-sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors. ResultsWe show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood-brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components. ConclusionOur data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/531162v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1549a3corg.highwire.dtl.DTLVardef@159f16aorg.highwire.dtl.DTLVardef@1f89500org.highwire.dtl.DTLVardef@fe6b67_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗