Biology subjects

van der Wal, R. J. P.

Publications and source records attributed to van der Wal, R. J. P..

3 recordsLinked to original sources

bioRxiv2025

Immune infiltration is linked to increased transcriptional activity and distinct metabolic profiles in chordomas

Chordomas are ultra-rare cancers from the axial skeleton with limited treatment options. Chordomas can exhibit immunogenic features, and immune checkpoint blockade has demonstrated clinical activity in some patients, yet the determinants of these responses remain poorly understood. We aimed to elucidate the biological basis of immunogenicity in chordomas through spatial transcriptomic and metabolomic analyses. We applied GeoMx digital spatial profiling to 15 chordomas, analyzing tumor and stromal compartments separately and comparing inflamed and non-inflamed tumors. Consecutive tissue sections were examined using MALDI-mass spectrometry imaging (MSI) at 20 {micro}m spatial resolution. Findings were further explored through immunohistochemistry analyses. To assess whether transcriptional activity in tumor cells was associated with interferon-{gamma} (IFN-{gamma}) signaling, we tested the effect of IFN-{gamma} treatment on chordoma cell lines. Digital spatial profiling of inflamed and non-inflamed chordomas revealed striking differences in both the cancer cell and stromal compartments. Increased immune infiltration was strongly associated with elevated transcriptional activity in cancer cells. MALDI-MSI revealed distinct metabolic signatures and pronounced glycogen accumulation in inflamed chordomas. Nevertheless, IFN-{gamma} stimulation of chordoma cell lines did not induce expression of TBXT (brachyury), the master transcriptional regulator of chordoma biology. Collectively, our findings reveal a strong association between the transcriptomic and metabolic activity in chordomas and their immunogenicity. However, the causal direction of this relationship remains to be determined. Nevertheless, these findings are highly relevant for patient stratification, particularly in the context of immunotherapeutic strategies.

cancer biology↗

bioRxiv2023

Multimodal profiling of chordoma immunity reveals distinct immune contextures

Chordomas are cancers from the axial skeleton presenting immunological hallmarks of unknown significance. In recent years, some clinical trials demonstrated that chordomas can respond to immunotherapy. We present a comprehensive characterisation of immunological features of 76 chordomas through application of a multimodal approach comprising transcriptional profiling, multidimensional immunophenotyping and TCR profiling. Chordomas generally presented an immune "hot" microenvironment in comparison to other sarcomas, as indicated by the immunologic constant of rejection transcriptional signature. We identified two distinct groups of chordomas based on T cell infiltration. The highly infiltrated group was further characterised by high dendritic cell infiltration and the presence of multicellular immune aggregates in tumours, whereas low T cell infiltration was associated with lower overall cell densities of immune and stromal cells. Interestingly, patients with higher T cell infiltration displayed a more pronounced clonal enrichment of the T cell receptor repertoire compared to those with low T cell counts. Furthermore, we observed that the majority of chordomas maintained HLA class I expression. Our findings shed light on the natural immunity against chordomas. Understanding their immune landscape could guide the development and application of immunotherapies in a tailored manner, ultimately leading to an improved clinical outcome for chordoma patients.

cancer biology↗

bioRxiv2022

WWP2 osteoarthritis risk allele rs1052429-A confers risk by affecting cartilage matrix deposition via hypoxia associated genes

ObjectiveTo explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele rs1052429-A on WWP2 expression in a human 3D in vitro model of cartilage. MethodsCo-expression behavior of WWP2 with genes expressed in lesioned OA articular cartilage (N=35 samples) was explored. By applying lentiviral particle mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N=8 donors) the effects of upregulation on cartilage matrix deposition was evaluated. Finally, we transfected primary chondrocytes with miR-140 mimics to evaluate whether miR-140 and WWP2 are involved in similar pathways. ResultsUpon performing Spearman correlations in lesioned OA cartilage, 98 highly correlating genes (|{rho}|>0.7) were identified. Among these genes, we identified GJA1, GDF10, STC2, WDR1, and WNK4. Subsequent upregulation of WWP2 on 3D chondrocyte pellet cultures resulted in a decreased expression of COL2A1 and ACAN and an increase in EPAS1 expression. Additionally, we observed a decreased expression of GDF10, STC2, and GJA1. Proteomics analysis identified 42 proteins being differentially expressed with WWP2 upregulation, which were enriched for ubiquitin conjugating enzyme activity. Finally, upregulation of miR-140 in 2D chondrocytes resulted in significant upregulation of WWP2 and WDR1. ConclusionsMimicking the effect of OA risk allele rs1052429-A on WWP2 expression initiates detrimental processes in the cartilage shown by a response in hypoxia associated genes EPAS1,GDF10, and GJA1 and a decrease in anabolic markers, COL2A1 and ACAN.

cell biology↗