Biology subjects

Bovee, J. V. M. G.

Publications and source records attributed to Bovee, J. V. M. G..

5 recordsLinked to original sources

bioRxiv2026

Machine Learning Analysis to Define Cell Lineage in Leiomyosarcoma

IntroductionCellular differentiation and lineage commitment are known to be associated with differences in DNA methylation. Leiomyosarcoma (LMS) is a tumor thought to originate from smooth muscle cells in the walls of vessels in the soft tissue (STLMS) or from the uterine myometrium (ULMS). Here, we identify the methylation signatures of normal smooth muscle cells from blood vessels and the uterine wall and compare these with those found in STLMS and ULMS. We hypothesized that these methylation signatures could be used to assign a smooth muscle subtype of origin to individual leiomyosarcomas, and that tumors of different origin would show biological differences with potential therapeutic relevance. MethodsTo define methylation profiles for smooth muscle from vessel walls versus those found in myometrium, EPIC methylation profiling was performed on DNA from 49 formalin-fixed paraffin-embedded (FFPE) normal smooth muscle samples. A supervised machine learning algorithm (Random Forest) was used to distinguish the methylation patterns of normal smooth muscle cells in vessel walls from those in the myometrium. The resulting classifier was applied to methylation data on 67 cases of LMS with corresponding bulk RNAseq data to identify which tumors showed a methylation signature most consistent with either blood vessel wall (LMSvessel) or myometrial smooth muscle (LMSwall). A custom signature matrix derived from scRNAseq data from 6 samples of LMS was used in CIBERSORTx analysis to compare the cellular composition of LMS cases with a vessel or uterine wall methylation signature. ResultsA high degree of correlation was found between the known site of origin for LMS (STLMS vs ULMS) and the methylation signature derived from different types of normal smooth muscle. LMSwall tumors compared to LMSvessel tumors had significantly higher activation of the PD-1 checkpoint pathway in RNAseq analysis. Digital flow cytometry by CIBERSORTx analysis showed an increased expression of transcriptomic signatures of several immune cell subtypes in LMSvessel tumors. ConclusionUsing a supervised machine learning approach we classified LMS samples as either showing a high similarity in methylation patterns to normal smooth muscle cells of either the vessel wall or the myometrium. We found a correlation between LMS showing either a "vessel" or "muscle wall" methylation signature and their site of origin, but notably we also identified some exceptions. When classified based on their methylation signature LMSwall and LMSvessel differed in their PD-1 pathway activation and in their predicted immune cell populations, suggesting potential implications for immunotherapeutic approaches.

cancer biology↗

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↗

bioRxiv2025

Divergent Therapeutic and Prognostic Impacts of Immunogenic Features in Undifferentiated Soft Tissue Sarcoma and Myxofibrosarcoma

Myxofibrosarcoma and undifferentiated soft tissue sarcoma (USTS) are genetically complex soft tissue sarcomas with distinct morphological features. Treatment typically involves surgery, often combined with neoadjuvant chemo- or radiotherapy. To better understand the immunobiology of these sarcomas and its associations with treatment response and prognosis, we performed transcriptomic and immunophenotypic profiling. RNA sequencing was performed on 13 USTS and 10 myxofibrosarcomas and immunological profiles were compared with soft tissue sarcoma data from The Cancer Genome Atlas (n = 206 including 44 USTS and 17 myxofibrosarcomas). Immune contextures were further evaluated in 16 USTS and 11 myxofibrosarcomas using imaging mass cytometry. Characterization of T cell and macrophage infiltration in tumors was further assessed in 23 USTS and 22 myxofibrosarcomas through multispectral immunofluorescence and immunohistochemical analysis. USTS and myxofibrosarcomas demonstrated immunogenic features compared to other soft tissue sarcomas, with subsets of USTS and myxofibrosarcomas demonstrating high T cell infiltration while USTS demonstrated a higher infiltration by myeloid cells as compared to myxofibrosarcoma. Prognostically, T cells and CD68+CD163+ macrophages were associated with metastasis-free survival in USTS but not in myxofibrosarcomas. Notably, in USTS, neoadjuvant radiotherapy appeared to induce cytotoxic T cell infiltration and depletion of myeloid cells, whereas these effects were not observed in myxofibrosarcomas. These findings highlight important differences in the immunobiology of USTS and myxofibrosarcomas with therapeutic and prognostic implications. These differences should be taken into account given the growing availability of immunotherapeutic options for treating patients with soft tissue sarcomas.

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

Interactions in CSF1-driven Tenosynovial Giant Cell Tumors

The majority of cells in Tenosynovial Giant Cell Tumor (TGCT) are macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. Treatment with inhibitors of the CSF1 pathway has been clinically effective. An autocrine loop was postulated where the neoplastic cells are stimulated through the CSF1 receptor (CSF1R) expressed on their surface. Here we show that the neoplastic cells themselves do not express CSF1R and therefore may be unaffected by current therapies. We identified a new marker for synoviocytes, GFPT2, that highlights the tumor cells in TCGT and is associated with activation of the YAP1/TAZ pathway. The neoplastic cells in TGCT are highly similar non-neoplastic synoviocytes. Finally, we provide molecular support for the osteoclast-like features of the giant cells in TGCT that correlate with the destructive effects of TGCT on bone.

cancer biology↗