Biology subjects

Vermeulen, L.

Publications and source records attributed to Vermeulen, L..

6 recordsLinked to original sources

bioRxiv2026

FFPERescuer: deep unsupervised domain adaptation for the reconstruction of gene expression profiles derived from formalin-fixed paraffin-embedded samples

Formalin-fixed paraffin-embedded (FFPE) tumor tissues often suffer from RNA degradation, posing a long-standing challenge for reliable transcriptomic profiling. Here, we propose FFPERescuer, a deep learning framework employing unsupervised domain adaptation, to rectify distorted gene expression data. FFPERescuer comprises a partial encoder that maps a small subset of genes to high-level representations and a decoder to reconstruct full gene expression profiles. On simulated data with varying noise levels, FFPERescuer faithfully recovered gene expression profiles, achieving high Pearson correlation coefficients (PCCs > 0.85) with the ground truth. In FF-FFPE-matched cohorts, FFPERescuer significantly enhanced expression profile concordance, with average PCCs increased by 23% (P < 0.05). Applying to cancer subtyping, FFPERescuer improved classification accuracy from 67% to 92%, recapitulated subtype-specific biological properties lost in the FFPE-derived data, and enhanced survival associations. Our studies provide a powerful framework for reliable transcriptomic profiling from FFPE-archived tumor samples that are widely available in the clinic.

bioinformatics↗

bioRxiv2026

Single-cell characterization of tumor immune landscapes in colorectal cancer humanized mice

Colorectal cancer (CRC) displays inter-patient heterogeneity in molecular tumor features and immune cell composition, which influence therapy response. Humanized immune system (HIS) mouse models offer a promising in vivo model to study human tumor-immune interactions, yet their ability to recapitulate the CRC tumor immune microenvironment at single-cell resolution remains incompletely defined. Here, we performed single-cell RNA sequencing of systemic and tumor-infiltrating human immune cells in HIS mice bearing human CRC tumors and benchmarked these data against reference datasets of healthy human spleens and primary CRC tumors. Major immune lineages and transcriptional programs characteristic of the human systemic immune compartment were identified, and HIS mouse tumors developed complex, human-like immune infiltrates. Tumor-infiltrating immune cells comprised diverse T cell, myeloid, natural killer, and B cell populations, including exhausted T cell states marked by expression of PDCD1, TIGIT, HAVCR2, LAG3, and CTLA4. We further demonstrate CRC consensus molecular subtype-associated spatial differences in immune infiltration. Collectively, our findings support the use of HIS mice as a relevant model for studying CRC immune landscapes and preclinical evaluation of immunomodulatory therapies.

cancer biology↗

bioRxiv2026

Apc truncation enforces optimal Wnt signalling during early intestinal tumourigenesis

Colorectal cancer (CRC) development is frequently initiated by inactivation of tumour suppressor gene adenomatous polyposis coli (APC), resulting in hyperactivation of the Wnt/ {beta}-catenin signalling pathway. The level of Wnt pathway activation is determined by the number of functional {beta}-catenin binding site repeats retained within the truncated APC protein. Accumulating evidence indicates that acquisition of the second APC mutational event is non-random and selects for mutations that confer a just right level of Wnt activity, suggesting that tumour initiation requires Wnt signalling to be maintained within a specific range. In this study, we investigated how specific Apc mutations modulate Wnt pathway activity and downstream cellular programs. Using CRISPR/Cas9 technology, we generated mouse intestinal organoid cultures harbouring distinct alterations in the number of {beta}-catenin binding repeats. We demonstrate a direct correlation between the number of retained repeats and Wnt signalling activity. Notably, organoids retaining higher numbers of functional repeats were subjected to selective pressure, resulting in the acquisition of additional mutations that lead to increased Wnt activity, consistent with the just right model. Transcriptomic analysis by RNA sequencing revealed that clones with distinct {beta}-catenin binding capacity exhibit differential transcriptional programs, including graded changes in cell cycle activity and a metabolic shift associated with progressive loss of {beta}-catenin binding repeats. Together, these findings reveal functional and metabolic heterogeneity among Apc- mutant cells, support the existence of selective pressures for optimal Wnt signalling during tumor initiation, and identify potential metabolic vulnerabilities that may be exploited for therapeutic intervention including interception of premalignant lesions.

cancer biology↗

bioRxiv2025

Acute Pericentral Liver Injury Induces a Novel Transient Hepatocyte Population

The liver exhibits robust regenerative capacity in response to injury, a property shaped by its essential metabolic and detoxification roles. While the mechanisms of regeneration following chronic liver injury have been extensively studied, the response during the early phases of acute injury remains poorly understood. Here, we employed a pericentral model of acute liver injury using carbon tetrachloride (CCl4) to investigate the initial hepatocyte response to damage. Through integration of single-nucleus multiome-sequencing, lineage tracing, spatial transcriptomics, and immunostaining, we identified a novel, transient population of damage-responsive SOX9+ pericentral hepatocytes. This population does not exhibit progenitor-like behavior but instead potentially mediates key aspects of early tissue repair. Specifically, SOX9+ pericentral hepatocytes engage in interactions with hepatic stellate cells and display migratory features associated with wound closure. Moreover, these cells exhibit an immune-related transcriptional signature and colocalize with liver macrophages at injury sites, suggesting a role in modulating immune responses. Our findings highlight a previously underappreciated function of SOX9 as a stress-responsive regulator of hepatocyte behavior and intercellular crosstalk during the early stages of acute liver injury.

cell biology↗

bioRxiv2024

The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation

The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.

developmental biology↗

bioRxiv2021

The extracellular matrix controls stem cell specification and tissue morphology in the developing and adult gut

The rapid renewal of the epithelial gut lining is fuelled by stem cells that reside at the base of intestinal crypts. In recent years, the signal transduction pathways and morphogens that regulate intestinal stem cell self-renewal and differentiation have been extensively characterised. In contrast, although extracellular matrix (ECM) components form an integral part of the intestinal stem cell niche, their direct influence on the cellular composition is less well understood. Here, we set out to systematically compare the effect of two major ECM classes, fibrillar collagen type I and the basement membrane, on the intestinal epithelium. We found that both collagen I and laminin-containing cultures allow growth of small intestinal epithelial cells with all differentiated and undifferentiated cell types present in both cultures, albeit at different ratios. Specific to the collagen culture was a subset of cells with a fetal-like gene expression program. In contrast, laminin, but not collagen IV, increased Lgr5+ stem cells and Paneth cells, and induced crypt-like morphology changes. The transition from a collagen culture to a laminin culture, resembles the gut development in vivo. Here, the ECM is dramatically remodelled by mesenchymal cells, which is accompanied by a specific and local expression of the laminin receptor ITGA6 in the crypt-forming epithelium. This laminin:ITGA6 signalling is essential for the stem cell induction and crypt formation in vitro. Importantly, deletion of laminin in the adult mouse results in a fetal-like epithelium with a marked reduction of adult intestinal stem cells. Overall, our data support the hypothesis that the formation of intestinal crypts is induced by an increased laminin concentration in the ECM.

cell biology↗