Transforming growth factor beta (TGF‐β), a multifunctional cytokine, plays critical roles in immune responses. However, the precise role of TGF‐β in colitis and colitis‐associated cancer remains poorly defined. Here, it is demonstrated that TGF‐β promotes the colonic inflammation and related tumorigenesis in the absence of Smad family member 4 (Smad4). Smad4 loss in intestinal epithelium aggravates colitis and colitis‐associated neoplasia induced by dextran sulfate sodium (DSS) and azoxymethane/dextran sulfate sodium (AOM/DSS), leading to over‐activated immune responses and increased TGF‐β1 levels. In Smad4‐deficient organoids, TGF‐β1 stimulates spheroid formation and impairs intestinal stem cell proliferation and lineage specification. YAP, whose expression is directly upregulated by TGF‐β1 after Smad4 deletion, mediates the effect of TGF‐β1 by interacting with Smad2/3. Attenuation of YAP/TAZ prevents TGF‐β1‐induced spheroid formation in Smad4^−/– organoids and alleviates colitis and colitis‐associated cancer in Smad4‐deficient mice. Collectively, these results highlight an integral role of the TGF‐β/Smad4 axis in restraining intestinal inflammation and tumorigenesis and suggest TGF‐β or YAP signaling as therapeutic targets for these gastrointestinal diseases intervention.

Background: Pulmonary neuroendocrine tumors (PNETs) are a special subtype of lung cancer with treatment methods are limited and prognostic indicators are insufficient. The preoperative systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) are effective tumor biomarkers that have important significance for the prognosis of many malignant tumors. However, there is no similar research on the predictive value of SII and PNI for operable PNETs. Our study aimed to clarify the predictive value of SII and PNI in PNETs patients after surgical resection. Methods: This study retrospectively analysed the relevant clinical data of PNETs patients who received surgical treatment from 2005 to 2015, which was obtained from patient’s clinical records, blood test results recorded on admission before surgical treatment, and follow-up by hospital records. Results: A total of 381 PNETs patients were enrolled in this study. Preoperative PNI was associated with age (P=0.001), T stage (P=0.001), tumor length (P=0.002), drinking status (P=0.013) and smoking status (P=0.049), while SII was significantly associated with T stage (P=0.001), tumor length (P=0.001) and TNM stage (P=0.001). There was significant difference between high SII and low PNI and worse OS of PENTs (P=0.001 and P<0.001). SII (P=0.002), neutrophil/lymphocyte ratio (NLR) (P<0.001), platelet/lymphocyte ratio (PLR) (P=0.001), lymph node metastasis (P<0.001), operation time (P=0.034<0.05), treatment (P<0.001) and PNI (P=0.044<0.05) were independent prognostic factors for PNETs identified by multivariate Cox regression analysis. Conclusions: High SII and low PNI indicated poor prognosis of patients with PNETs. Both of SII and PNI can predict the prognosis of PNETs and stratify patients for better treatment.

Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the intestinal epithelium is well appreciated, the direct effect of BMP on intestinal stromal cells is poorly understood. Here, we show that disruption of BMP signaling by genetic ablation of Alk3 or Smad4 expands the stromal cell pool, the mucosa tumefaction, and colonic polyposis in the large intestine. Interleukin (IL) secretion by stromal cells is notably increased, including IL-1, IL-11, and IL-17. Specifically, IL-1 and IL-17a hyperactivate the mucin production by goblet cells through nuclear factor κB signaling, and abnormal mucin accumulation results in the morphological changes, epithelial barrier destruction, and polyposis development. Together, our results provide an insight into the role of BMP signaling in intestinal stromal cells to regulate epithelium function. This study further highlights the role of mucin-producing goblet cells in intestinal homeostasis and colitis development.

Organoid technology provides a transformative approach to understand human physiology and pathology, offering valuable insights for scientific research and therapeutic development. Human gastric organoids, in particular, have gained significant interest for applications in disease modeling, drug discovery, and studies of tissue regeneration and homeostasis. However, the lack of standardized quality control has limited their extensive clinical applications. The “Human Gastric Organoids” is part of a series of guidelines for human gastric organoids in China, which establishes comprehensive standards on terminology, technical specifications, testing methods, inspection rules, usage instructions, labeling, transportation, and storage, developed by experts from the Chinese Society for Cell Biology and its branch societies. Released on October 29, 2024, this guideline aims to establish standardized protocols, enhance institutional practices, and promote international standardization for clinical and research applications of human gastric organoids.

Lgr5 ⁺ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5 ⁺ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5 ⁺ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.