Glioblastoma (GB) is the most frequent and aggressive type of glioma. The lack of reliable GB models, together with its considerable clinical heterogeneity, has impaired a comprehensive investigation of the mechanisms that lead to tumorigenesis, cancer progression, and response to treatments. Recently, 3D cultures have opened the possibility to overcome these challenges and cerebral organoids are emerging as a leading-edge tool in GB research. The opportunity to easily engineer brain organoids via gene editing and to perform co-cultures with patient-derived tumor spheroids has enabled the analysis of cancer development in a context that better mimics brain tissue architecture. Moreover, the establishment of biobanks from GB patient-derived organoids represents a crucial starting point to improve precision medicine therapies. This review exemplifies relevant aspects of 3D models of glioblastoma, with a specific focus on organoids and their involvement in basic and translational research.

Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a “fetal-like” regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.

The colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that upon injury and subsequent inflammatory response, IFN-γ drives widespread epithelial remodeling. IFN-γ promotes rapid apoptotic extrusion of fully differentiated surface colonocytes, while simultaneously causing differentiation of crypt-base stem and progenitor cells towards a colonocyte-like lineage. However, unlike homeostatic colonocytes, these IFN-γ-induced colonocytes neither respond to nor produce BMP-2 but retain regenerative capacity. The reduction of BMP-2-producing epithelial surface cells causes a remodeling of the surrounding mesenchymal niche, inducing high expression of HGF, which promotes proliferation of the IFN-γ-induced colonocytes. This mechanism of lineage replacement and subsequent remodeling of the mesenchymal niche enables tissue-wide adaptation to injury and efficient repair.

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RARγ activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1 ^F254E255 is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

In the gastrointestinal tract, Wnt and BMP signals control Lgr5 ⁺ stem cell activity during homeostasis, whereas injury elicits an Lgr5 -independent, fetal-like regenerative program driven by YAP. Helicobacter pylori ( H. pylori ) infection activates YAP, but whether fetal-like reprogramming contributes to gastric pathology, and what drives it, has remained unclear. Here we show that H. pylori -induced gland hyperplasia is accompanied by YAP-dependent fetal-like transcriptional response and loss of epithelial BMP signaling. Epithelial BMP inhibition alone is sufficient to induce this program in vivo, through an epithelial–immune–stromal cascade: BMP-deficient epithelial cells secrete chemokines that recruit IL-1β-producing immune cells, and IL-1β drives enrichment of pro-regenerative fibroblasts producing prostaglandin E2. In gastric epithelial–stromal assembloids, IL-1β elicits stromal prostaglandin E2 production and subsequent epithelial YAP activation. Stromal deletion of the IL-1 receptor abrogates H. pylori -driven reprogramming and pathology. These data define a cascade that converts BMP loss into a fetal-like regenerative state and shapes H. pylori -associated gastric disease.