Hans Clevers

Modeling reptile virus infection in vitro using Python regius airway organoids

Interferon-γ selectively promotes survival of alveolar progenitor cells in a human lung organoid model

Discovery of a secreted Bacteroides fragilis mucinase that cleaves mucins with bis-T O-glycans through a carbohydrate binding module-dependent mechanism

A Two-Dimensional Organoid Culture on Invasin or Basement Membrane Extract to Study Host-Bacteria Interactions

Human gut M cells resemble dendritic cells and present gluten antigen

Microfold (M) cells are rare intestinal epithelial cells that reside in the follicle-associated epithelium of Peyer’s patches1. M cells transport luminal antigens to submucosal antigen-presenting cells2,3. These insights primarily derive from transmission electron microscopy and studies using genetically modified mice2–4. Here we establish an intestinal organoid model to study human M cells and reconstruct the differentiation trajectory of M cells through transcriptome profiling. The results indicate that as well as facilitating luminal antigen transport, human M cells also directly present antigens via the class II major histocompatibility complex (MHC-II). Notably, the related enterocytes only express MHC-II in chronic inflammatory states and do not express typical dendritic cell markers. Human M cells physiologically express a gene profile that resembles that of dendritic cells. Similar to dendritic cells, M cell development is induced by RANKL and CSF2 and requires the transcription factors SPIB and RUNX2. HLA-DQ2.5 M cells process and present gluten antigen as demonstrated in organoid–T cell co-culture assays. These findings suggest that M cells may have a central role in coeliac disease. An intestinal organoid model recapitulates human microfold (M) cell function and transcriptomic profiling and biochemical assays demonstrate that M cells uptake and present antigens to the immune system via the class II major histocompatibility complex.

Tripotent Lgr5 stem cells in the posterior tongue generate lingual, taste, and salivary gland lineages

Hepatic zonation determines tumorigenic potential of mutant β-catenin

Oncogenic mutations in phenotypically normal tissue are common across adult organs 1,2 . This suggests that multiple events need to converge to drive tumorigenesis and that many processes such as tissue differentiation may protect against carcinogenesis. WNT–β-catenin signalling maintains zonal differentiation during liver homeostasis 3,4 . However, the CTNNB1 oncogene—encoding β-catenin—is also frequently mutated in hepatocellular carcinoma, resulting in aberrant WNT signalling that promotes cell growth 5,6 . Here we investigated the antagonistic interplay between WNT-driven growth and differentiation in zonal hepatocyte populations during liver tumorigenesis. We found that β-catenin mutations co-operate with exogenous MYC expression to drive a proliferative translatome. Differentiation of hepatocytes to an extreme zone 3 fate suppressed this proliferative translatome. Furthermore, a GLUL and Lgr5 -positive perivenous subpopulation of zone 3 hepatocytes were refractory to WNT-induced and MYC-induced tumorigenesis. However, when mutant CTNNB1 and MYC alleles were activated sporadically across the liver lobule, a subset of mutant hepatocytes became proliferative and tumorigenic. These early lesions were characterized by reduced WNT pathway activation and elevated MAPK signalling, which suppresses zone 3 differentiation. The proliferative lesions were also dependent on IGFBP2–mTOR–cyclin D1 pathway signalling, in which inhibition of either IGFBP2 or mTOR suppressed proliferation and tumorigenesis. Therefore, we propose that zonal identity dictates hepatocyte susceptibility to WNT-driven tumorigenesis and that escaping WNT-induced differentiation is essential for liver cancer.

A Collection of Patient-Derived Intestinal Organoid Lines Reveals Epithelial Phenotypes Associated with Genetic Drivers of Pediatric Inflammatory Bowel Disease

A single-chain derivative of an integrin-activating antibody potentiates organoid growth in Matrigel and collagen hydrogels

Current methods of culturing human epithelial organoids from adult stem cells may not be compatible with clinical applications as they rely on xenogeneic, chemically undefined or non-standardized components such as the basement membrane extract Matrigel. Matrigel provides a source of extracellular matrix molecules, including laminins and collagen IV, which interact with β1 integrins expressed on organoid cells. Here we describe a single-chain (sc) version of antibody TS2/16 that allosterically activates integrin β1 function in organoids. The addition of monomeric scTS2/16 to organoid medium results in up to a fivefold increase in the yield of all gastrointestinal organoids grown in Matrigel. Moreover, scTS2/16 supports a six- to sevenfold increase in the yield of these organoids when cultured in collagen I hydrogels, both in 3D and 2D. Collagen I is well defined, available in clinical-grade formulations and, when combined with scTS2/16, may support the clinical application of epithelial organoids derived from gastrointestinal tissues and other epithelial sources.

FER kinase governs invasive growth of head and neck squamous cell carcinoma through dynamic control of growth factor receptor activity

• FER, a non-receptor tyrosine kinase, is prognostic in HPV-negative HNSCC and essential for growth factor receptor–dependent invasion. • In patient-derived tumor organoid models, FER controls MET and EGFR oncogenic signaling required for invasion in 3D Collagen-I extracellular matrix. • FER regulates ligand-dependent endocytic transport dynamics during HNSCC progression. • Genetic FER loss or FER-targeted PROTAC therapy suppresses invasion and metastasis in PDO-based xenograft models. • FER represents a promising therapeutic target for clinical intervention in aggressive HNSCC. Promiscuous activation of growth factor receptors drives sustained MAP kinase signaling, which reinforces oncogene addiction in HPV-negative head and neck squamous cell carcinoma (HNSCC). This feature promotes invasive growth, complicating surgical resection and contributing to high rates of local relapse and poor patient outcomes. Current treatment strategies for locally advanced or non-resectable tumors targeting single growth factor receptors offer limited therapeutic benefit, underscoring the need for alternative targets. Using patient-derived tumor organoid (PDO) models of invasive HNSCC, we demonstrate that FER, a non-receptor tyrosine kinase that correlates with poor survival in HNSCC patients, is essential for growth factor receptor dependent invasive growth in Collagen-I extracellular matrix (ECM) networks. In this setting, FER promotes phosphorylation of EGFR-Y1068 and MET-Y1234/5. Additionally, FER controls ligand-dependent endocytic transport velocity, demonstrating a multifactorial regulation of proximal GFR activation during HNSCC invasion. Finally, genetic loss of function experiments or a FER-specific PROteolysis-TArgeting Chimera (PROTAC) strategy in PDO-based xenograft mouse models, demonstrate that FER is essential for invasive growth and metastasis of HNSCC. In sum, we propose that FER is an indiscriminate regulator of proximal GFR activation in HNSCC, a mechanism that may foster oncogene addition, thereby leading to invasive growth and metastasis. Based on its oncogenic roles and correlations with poor patient prognosis, we nominate FER as a potential candidate for targeted clinical intervention of HNSCC.

Invasin-functionalized PIC hydrogels enable long-term 3D culture of epithelial organoids

CleversCancer Heterogeneity and Plasticity

Advancing Cancer Biology: Highlights from the 2025 FASEB SRC on Cellular Plasticity in Cancer

The inaugural FASEB Science Research Conference (SRC) on Cellular Plasticity in Cancer was held in May 2025 in Hong Kong SAR, China. This event brought together leading experts to discuss cutting-edge research centered on cancer cell plasticity. The conference featured comprehensive presentations covering a broad spectrum of topics, including oncofetal reprogramming in tumor development and progression, mechanisms regulating cancer cell plasticity, metabolic reprogramming and its role in tumor progression, cancer cell plasticity during metastasis, cancer stem cell programs within the tumor microenvironment, tumor plasticity and immune evasion, as well as innovative therapeutic strategies aimed at targeting stem cell-like states, modulating cancer cell states, and effectively controlling disease progression. It is anticipated that the insights gained from this meeting will catalyze further advancements in cancer biology and therapy.

BEST4/CA7⁺ and goblet cells are interdependent regulators of intestinal mucus homeostasis

Epithelial tension controls intestinal cell extrusion

Controlling Intestinal Organoid Polarity using Synthetic Dynamic Hydrogels Decorated with Laminin‐Derived IKVAV Peptides

Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition

Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy

Fetal reversion from diverse lineages sustains the intestinal stem cell pool and confers stress resilience

Plasticity is a central mechanism underlying the robust regenerative capacity of the intestinal epithelium. Two major plasticity have been described: spatial plasticity, in which differentiated cells revert to crypt base columnar cells (CBCs), and fetal reversion into revival stem cells (revSCs). However, the relationship among these two stem cell populations and differentiated cells remains to be clarified. Here, we demonstrated the bidirectional interconversion between CBCs and revSCs. Using lineage tracing, injury models and villus culture, we show that absorptive enterocytes can reprogram into revSCs and regenerate CBCs. These findings position fetal reversion as an entry point to spatial plasticity, establishing a regenerative hierarchy where CBCs, revSCs, and enterocytes collectively orchestrate intestinal repair. Furthermore, we identified revSCs as a highly stress-tolerant stem cell population, whose emergence is crucial for preserving the stem cell pool. Our results establish fetal reversion as a cellular escape mechanism safeguarding epithelial regeneration under inflammatory conditions.

Novel Findings in Pediatric and Adolescent Patients With Cancer and a Germline SMARCA4 Variant

INTRODUCTION: SMARCA4 is a known susceptibility gene for malignant rhabdoid tumors (MRT) in children and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) in young females and women. Recently, a novel association between germline SMARCA4 variants and predisposition to neuroblastoma was proposed. METHODS: We present a single-center study summarizing the clinical and genetic data of pediatric and adolescent cancer patients with a germline SMARCA4 variant diagnosed with and/or treated for an MRT, SCCOHT, or neuroblastoma. RESULTS: We identified nine patients with germline SMARCA4 variants, including one patient with an MRT, four patients with a SCCOHT, and four patients with a neuroblastoma. We observed two novel pathogenic SMARCA4 variants that were initially missed using diagnostic testing: a low-mosaic pathogenic SMARCA4 variant in the patient with an MRT, and a germline SMARCA4 partial gene deletion, encompassing the promoter region, in a patient with a SCCOHT. The patients with neuroblastoma in our cohort had a strikingly old age at diagnosis (range: 10-22 years old). In three of four patients with neuroblastoma, the germline SMARCA4 variant was a variant of unknown significance (VUS). In two of their neuroblastomas, we observed loss of heterozygosity at the SMARCA4 locus, and loss of BRG1 expression was found in one of these. CONCLUSIONS: This study highlights that awareness is needed for easy-to-miss germline variants in SMARCA4 and that knowledge about variant types, cancer spectrum, and cancer penetrance in individuals with a germline SMARCA4 variant is still evolving.

A collection of patient-derived intestinal organoid lines reveals epithelial pheno-types associated with genetic drivers of pediatric inflammatory bowel disease