Biology subjects

Ormanns, S.

Publications and source records attributed to Ormanns, S..

5 recordsLinked to original sources

bioRxiv2026

Ex Vivo Assay for Organ-Specific Cancer Cell Invasion

BackgroundMetastasis is the leading cause of cancer-related mortality, yet experimental models often fail to recapitulate the tissue-specific microenvironments that shape metastatic dissemination. While in vivo systems provide physiological relevance, they are poorly suited for mechanistic studies. Conversely, conventional in vitro assays lack the organ-specific extracellular matrix (ECM) context that critically regulates invasive behavior. There is therefore a need for accessible models that balance biological relevance with experimental feasibility. ResultsIn this study, we developed an ex vivo invasion platform based on mild detergent decellularization of mouse organs followed by vibratome slicing. This approach generates optically transparent lung, liver, and intestine ECM scaffolds that preserve native matrix architecture, mechanical properties, and retain biochemical hallmarks of their tissues of origin. Organ-derived matrices were integrated into standard microfluidic channels and analyzed using conventional fluorescence microscopy to enable quantitative assessment of cancer cell invasion. Benchmarking with breast cancer cell lines of defined invasive capacity, we could demonstrate the robustness and biological relevance of the system. Non-invasive MCF7 cells failed to infiltrate any organ scaffold, whereas highly invasive MDA-MB-231 cells exhibited pronounced organ-specific invasion. These cells preferentially invaded lung and liver ECM while showing minimal invasion of intestinal scaffolds, recapitulating clinically observed metastatic tropism. Quantitative invasion rates closely matched values previously reported in vivo using intravital microscopy. ConclusionsThis ex vivo organ-derived ECM platform provides a scalable, cost-effective, and experimentally accessible system to study ECM-driven determinants of metastatic invasion. By preserving tissue-specific matrix cues while reducing reliance on animal models, this approach provides a powerful tool to interrogate ECM-driven determinants of metastasis and to evaluate potential therapeutic interventions.

cancer biology↗

bioRxiv2026

Genotype-phenotype mapping identifies fetal-like CD55+ immunoregulatory cancer cells as mediators of immune escape in colorectal cancer

Immune evasion is a defining feature of advanced colorectal cancer (CRC), yet the cellular mechanisms linking cancer cell states to immune suppression remain poorly understood. To systematically map tumour-immune interactions in advanced CRC, we modelled recurrent human CRC mutations using a multiplex CRISPR-based genetically engineered mouse model platform. The resulting 20 models recapitulate key stages, genetic routes and histopathological features of human CRC, while single-cell transcriptomics reveals extensive disease complexity across models. Profiling of the epithelial tumour compartment identified a population of fetal-like immunoregulatory cancer cells (IRCs) characterized by interferon-{gamma} and MAPK activity. IRCs are marked by expression of the membrane-bound complement regulatory protein CD55. Mechanistically, CD55 protects IRCs from immune surveillance and complement-mediated lysis. Together, these findings reveal a cancer cell-immune interface that promotes immune evasion in advanced CRC.

cancer biology↗

bioRxiv2026

WNT-driven immune evasion promotes malignant transformation of BRAF-mutant colorectal cancer

BRAF-mutant colorectal cancer (CRC) constitutes a molecularly and clinically distinct subtype with poor prognosis and resistance to standard therapies, representing a major unmet clinical need. Arising from the serrated pathway of colorectal carcinogenesis rather than the classical adenoma-carcinoma sequence, this subgroup remains relatively understudied yet displays a more aggressive disease course. To investigate the progression of serrated CRC, we generated multiple genetically engineered mouse models (GEMMs) of BRAF-mutant, microsatellite-stable (MSS) CRC that closely recapitulate human disease. Our findings demonstrate that WNT-pathway activation via APC- or CTNNB1-mutations, but not RNF43-loss, initiates serrated CRC by suppressing immune-mediated tumor surveillance. Mechanistically, WNT-signaling drives distinct alterations in T cell phenotypes within the tumor microenvironment, enabling tumor progression. Together, these data indicate that WNT-signaling mediates immune escape during the malignant transformation of BRAF-mutant CRC.

cancer biology↗

bioRxiv2025

PCSK9 dependent cholesterol acquisition and utilization underlies metastatic organ preference in pancreatic cancer.

To grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs1. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there are undefined. We identified Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) as predictive of colonization of the liver versus lungs by integrating datasets describing the metastatic tropism of human PDAC cell lines2, with in vivo metastasis modeling in mice and gene expression correlation analysis. PCSK9 is a negative regulator of low density lipoprotein(LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells exhibit strong preference for colonizing LDL-rich liver tissue. Cholesterol taken up by liveravid PCSK9-low cells is converted into the signaling oxysterol, 24(S)-hydroxycholesterol, which reprograms the surrounding microenvironment to induce nutrient release from neighboring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates, chiefly, 7dehydrodesmosterol and 7-dehydrocholesterol, with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing PCSK9 levels redirected liver-avid cells to the lung whereas its ablation drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC.

cancer biology↗

bioRxiv2025

IBDome: An integrated molecular, histopathological, and clinical atlas of inflammatory bowel diseases

Multi-omic and multimodal datasets with detailed clinical annotations offer significant potential to advance our understanding of inflammatory bowel diseases (IBD), refine diagnostics, and enable personalized therapeutic strategies. In this multi-cohort study, we performed an extensive multi-omic and multimodal analysis of 1,002 clinically annotated patients with IBD and non-IBD controls, incorporating whole-exome and RNA sequencing of normal and inflamed gut tissues, serum proteomics, and histopathological assessments from images of H&E-stained tissue sections. Transcriptomic profiles of normal and inflamed tissues revealed distinct site-specific inflammatory signatures in Crohns disease (CD) and ulcerative colitis (UC). Leveraging serum proteomics, we developed an inflammatory protein severity signature that reflects underlying intestinal molecular inflammation. Furthermore, foundation model-based deep learning accurately predicted histologic disease activity scores from images of H&E-stained intestinal tissue sections, offering a robust tool for clinical evaluation. Our integrative analysis highlights the potential of combining multi-omics and advanced computational approaches to improve our understanding and management of IBD.

molecular biology↗