Biology subjects

Kommoss, F. K.

Publications and source records attributed to Kommoss, F. K..

4 recordsLinked to original sources

bioRxiv2024

Spatial single cell transcriptomic analysis of a novel DICER1 Syndrome GEMM informs the cellular origin and developmental hierarchy of associated sarcomas

DICER1 syndrome predisposes children and young adults to tumor development across various organs. Many of these cancers are sarcomas, which uniquely express the RNase IIIb domain-deficient form of DICER1 and exhibit consistent histological and molecular similarities regardless of their anatomical origins. To uncover their cellular origin and developmental hierarchy, we established a lineage-traceable genetically engineered mouse model that allows for precise activation of Dicer1 mutations in Hic1+ mesenchymal stromal cells. This model resulted in the development of renal tumors closely mirroring human DICER1 sarcoma histologically and molecularly. Single-cell transcriptomics coupled with targeted spatial gene expression analysis revealed a Hic1+ progenitor population marked by Pdgfra, Dpt, and Mfap4, corresponding to universal fibroblasts of steady-state kidneys. These fibroblastic progenitors exhibit the capacity to undergo rhabdomyoblastic differentiation or transition to highly proliferative anaplastic sarcoma. Investigation of patient samples identified analogous cell states. This study uncovers a fibroblastic origin for DICER1 sarcoma and provides a faithful model for mechanistic investigation and therapeutic development for tumors within the rhabdomyosarcoma spectrum.

cancer biology↗

bioRxiv2024

Integrative Imaging of Lung Micro Structure: Amplifying Classical Histology by Paraffin Block μCT and same-slide Scanning Electron Microscopy

Classical histopathology of formalin fixed and paraffin embedded (FFPE) tissue using light microscopy (LM) remains the undisputed gold standard in biomedical microstructural lung tissue analysis. To extend this method, we developed an integrative imaging and processing pipeline which adds 3D context and screening capabilities by micro-CT (CT) imaging of the entire paraffin block and adds ultrastructural information by correlative same-slide scanning electron microscopy (SEM). The different modalities are integrated by elastic registration to provide hybrid image datasets. Without compromising standard light microscopic readout, we overcome the limitations of conventional histology by combining and integrating several imaging modalities. The biochemical information contained in histological and immunohistological tissue staining is embedded into the 3D tissue configuration and is amplified by adding ultrastructural visualization of features of interest. By combining CT and conventional histological processing, specimens can be screened, and specifically preselected areas of interest can be targeted in the subsequent sectioning process. While most of the CT data shown in the manuscript was acquired at a Synchrotron, we further demonstrate that our workflow can also by applied using X-ray microscopy.

pathology↗

bioRxiv2023

Landscape of super-enhancers in small cell carcinoma of the ovary, hypercalcemic type and efficacy of targeting with natural product triptolide

PurposeSmall cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare form of ovarian cancer affecting young women and girls. SCCOHT is driven by loss of both SWI/SNF ATPases SMARCA4 and SMARCA2, having major effects on enhancer landscapes. Super-enhancers are a distinct subset of enhancer clusters frequently associated with oncogenes in cancer. Experimental DesignSCCOHT cell lines and PDX models were interrogated for super-enhancer landscape with H3K27ac CUT&RUN integrated with RNAseq data for associated oncogene analysis. IHC staining and drug efficacy studies in PDX models demonstrate clinical translatability. ResultsHere we discovered key distinctions between SWI/SNF chromatin occupancy following SMARCA4 restoration at enhancer vs. super-enhancer sites and characterized putative oncogene expression driven by super-enhancer activity. SCCOHT super-enhancer target genes were particularly enriched in developmental processes, most notably nervous system development. We found high sensitivity of SCCOHT cell lines to triptolide, a small molecule that targets the XPB subunit of the transcription factor II H (TFIIH) complex, found at super-enhancers. Triptolide inhibits expression of many super-enhancer associated genes, including oncogenes. Notably, SALL4 expression is significantly decreased following short triptolide treatment, and its RNA expression was high in SCCOHT tumors relative to other ovarian cancers. In SCCOHT patient-derived xenograft models, triptolide and its prodrug derivative minnelide are particularly effective in inhibiting tumor growth. ConclusionsThese results demonstrate the key oncogenic role of super-enhancer activity following epigenetic dysfunction in SCCOHT, which can be effectively targeted through inhibition of its functional components, such as TFIIH inhibition with triptolide. Statement of Translational RelevanceThis work identifies a potential therapeutic strategy for small cell carcinoma of the ovary-hypercalcemic type (SCCOHT), a rare and aggressive ovarian cancer affecting young women and children. This study highlights the role of the loss of SWI/SNF ATPase SMARCA4 in altering super-enhancers to promote high oncogene expression. We discovered that SCCOHT cells exhibited high sensitivity to triptolide, a small molecule derived from Tripterygium wilfordii, which targets the XPB subunit of the transcription factor II H (TFIIH) complex found at super-enhancers. Triptolide inhibits the expression of super-enhancer-associated genes, including oncogenes like SALL4, which is highly expressed in SCCOHT. Moreover, in SCCOHT patient-derived xenograft models, triptolide and its derivative minnelide effectively inhibited tumor growth. These findings suggest that targeting super-enhancer activity could be a promising therapeutic approach for SCCOHT, offering potential clinical benefits to patients who currently face limited treatment options and poor outcomes.

cancer biology↗

bioRxiv2022

An autoregulatory feedback loop converging on H2A ubiquitination drives synovial sarcoma

The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of mSWI/SNF complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the SSX C-terminus, via its SSXRD domain, directs SS18-SSX chromatin binding independently of SS18. SSXRD specific targeting is mediated by interaction with mono ubiquitinated H2A (H2AK119ub1) and histone MacroH2A with which the fusion overlaps genome wide. Variant Polycomb Repressive Complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C-terminus not only depends on H2AK119ub1 for localization but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results reveal an SSX/PRC1 autoregulatory feedback loop that reinforces fusion chromatin binding and therefore its oncogenic activity, and could play a role in a wider range of cancers and physiological settings where SSX proteins are overexpressed.

cancer biology↗