Biology subjects

Verhagen, M.

Publications and source records attributed to Verhagen, M..

4 recordsLinked to original sources

bioRxiv2026

Inflammation-driven reprogramming of goblet cells underlies the onset of serrated adenomas in colon cancer

In the context of inflammation, fully committed and post-mitotic cell lineages can initiate intestinal tumorigenesis in the mouse through dedifferentiation and acquisition of revival stem cell (RSC) features1,2. Likewise, by means of machine-learning analysis of whole-genome mutation spectra, the secretory goblet cell was predicted as the most frequent cell-of-origin (COO) of colon cancer in inflammatory bowel disease (IBD) patients2. Of note, even among sporadic (non-IBD) colon cancer patients, goblet cells were predicted as the most common differentiated COO of cancer in the colonic epithelium2, suggestive of the main role played by diet-induced inflammation in the onset of a large proportion of malignancies of the large bowel. However, how goblet cells respond to inflammation and reprogram their identity to become potential tumor-initiating cells remains unclear. Here, by taking advantage of publicly available single-cell RNAseq data from colonic tissues of ulcerative colitis (UC) patients3, we have characterized the inflammation-driven reprogramming of goblet cells. By means of an RNA velocity-based computational approach, we show that the mucus-producing goblet cells acquire an aberrant proliferative state earmarked by MUC5AC+ expression. Trajectory analysis of serrated adenoma cells4 reveal aberrant goblet cells as an intermediate state in the transition to revival stem cells, notably more common in BRAF-mutant cases. In support of these findings, COO predictions using whole-genome mutation spectra from a cohort of sporadic colon cancers5 connect tumors with a predicted goblet origin to BRAF mutations and reveal transcriptional remnants of the aberrant goblet cell state.

Cancer Biology↗

bioRxiv2020

Phenotypic plasticity and partial EMT underlie local invasion and distant metastasis in colon cancer

Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphologic and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental models. Here, we identified a subpopulation of phenotypic plastic colon cancer cells: EpCAMlo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAMlo bulk and single-cell RNAseq analysis indicated 1. enhanced Wnt/{beta}-catenin signaling, 2. a broad spectrum of degrees of EMT activation including hybrid E/M states (partial EMT) with highly plastic features, and 3. high correlation with the CMS4 subtype, accounting for colon cancer cases with poor prognosis and a pronounced stromal component. Of note, a signature of genes specifically expressed in EpCAMlo cancer cells is highly predictive of overall survival in tumors other than CMS4, thus highlighting the relevance of quasi-mesenchymal tumor cells across the spectrum of colon cancers. Enhanced Wnt and the downstream EMT activation represent key events in eliciting phenotypic plasticity along the invasive front of primary colon carcinomas. Distinct sets of epithelial and mesenchymal genes define transcriptional trajectories through which state transitions arise. pEMT cells, often earmarked by the extracellular matrix glycoprotein SPARC together with nuclear ZEB1 and {beta}-catenin along the invasive front of primary colon carcinomas, are predicted to represent the origin of these (de)differentiation routes through biologically-distinct cellular states, and to underlie the phenotypic plasticity of colon cancer cells.

cancer biology↗

bioRxiv2019

Engineered Living Materials based on Adhesin-mediated Trapping of Programmable Cells

Engineered living materials have the potential for wide-ranging applications such as biosensing and treatment of diseases. Programmable cells provide the functional basis for living materials, however, their release into the environment raises numerous biosafety concerns. Current designs that limit the release of genetically engineered cells typically involve the fabrication of multi-layer hybrid materials with sub-micron porous matrices. Nevertheless the stringent physical barriers limit the diffusion of macromolecules and therefore the repertoire of molecules available for actuation in response to communication signals between cells and their environment. Here, we engineer a first-of-its-kind living material entitled Platform for Adhesin-mediated Trapping of Cells in Hydrogels (PATCH). This technology is based on engineered E. coli that displays an adhesion protein derived from an Antarctic bacterium with high affinity for glucose. The adhesin stably anchors E. coli in dextran-based hydrogels with large pore diameters (10-100 m) and reduces the leakage of bacteria into the environment by up to 100-fold. As an application of PATCH, we engineered E. coli to secrete lysostaphin via the Type 1 Secretion System and demonstrated that living materials containing this E. coli inhibit the growth of S. aureus, including the strain resistant to methicillin (MRSA). Our tunable platform allows stable integration of programmable cells in dextran-based hydrogels without compromising free diffusion of macromolecules and could have potential applications in biotechnology and biomedicine.

synthetic biology↗

bioRxiv2017

Causal Associations Between Body Mass Index and Mental Health: A Mendelian Randomization Study

BackgroundBody Mass Index (BMI) is negatively correlated with subjective well-being and positively correlated with depressive symptoms. Whether these associations reflect causal effects or confounding is unclear.\n\nMethodsWe examined causal effects between BMI and subjective well-being/depressive symptoms with bi-directional, two-sample Mendelian randomization using summary-level data from large genome-wide association studies. Genetic variants robustly related to the exposure variable acted as instrumental variable (two thresholds were used; p<5e-08 and p<1e-05). These instruments were then associated with the outcome variable. Pleiotropy was corrected for by two sensitivity analyses.\n\nResultsSubstantial evidence was found for a causal effect of BMI on mental health, such that a higher BMI decreased subjective well-being and increased depressive symptoms. No consistent evidence was found for causality in the other direction.\n\nConclusionsThis study provides support for a higher BMI causing poorer mental health. Further research should corroborate these findings and consider non-linear effects and sex differences.

genetics↗