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LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach 1 , but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5 + intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway 2 . However, the contribution of pyloric LGR5 + stem cells to gastric cancer following dysregulation of the WNT pathway—a frequent event in gastric cancer in humans 3 —is unknown. Here we use comparative profiling of LGR5 + stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5 + compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5 + cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic. AQP5 is identified as a marker for pyloric stem cells in humans and mice, and stem cells in the AQP5 + compartment are shown to be a source of invasive gastric cancer in mouse models.

Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent, Lgr5 -expressing stem/progenitor cells are essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ Lgr5-2A-EGFP/CreERT2/DTR mouse models to identify Lgr5 -expressing cells in the developing uterus and to evaluate their stem cell identity and function. Lgr5 is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5 high cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5 neg epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5 high stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5 + stem/progenitor cells to uterine disorders. Uterine gland development is essential for successful embryo implantation, decidua formation and placental development. Here the authors demonstrate that neonatal Wnt-dependent Lgr5 expressing stem/progenitor cells at the tips of developing glands are indispensable for uterine gland development.

Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia–carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(–), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v‐xCT system in the development of spasmolytic polypeptide‐expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v+ metaplastic cells manifested upregulation of xCT expression compared with CD44v− cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT‐dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v‐xCT could thus prove effective for prevention or attenuation of the CD44v‐dependent development of preneoplastic lesions and cancer.

Colorectal cancer (CRC) is a substantial global health concern due to its limited treatment options, especially for oxaliplatin (L-OHP) regimen resistance. This study used organoid-based screening methodologies to evaluate drug responses in CRC while validating the approach with patient-derived CRC organoids and investigating potential biomarkers. Patient-derived organoids were created from CRC surgical specimens, and drug screening were performed. Selected organoids with high and low L-OHP sensitivity underwent next-generation sequencing (NGS), and in vivo experiments using xenotransplantation were used to validate in vitro results. Moreover, the clinical application of homologous recombination deficiency (HRD) as a biomarker was investigated. Organoid drug screening revealed differences in L-OHP sensitivity among 34 patient-derived CRC organoids, and NGS deemed HRD as a potential biomarker. In vivo experiments validated the correlation between HRD status and L-OHP sensitivity, and clinical data suggested the potential of HRD as a biomarker for recurrence-free survival in patients treated with L-OHP. Additionally, HRD exhibited potential as a biomarker for other platinum agents and poly (ADP-ribose) polymerase inhibitors in CRC. The study underscores HRD as a potential biomarker for predicting L-OHP sensitivity, expanding its application to other drugs in CRC. Organoid screening is reliable, providing insights into the intricate association between genetic features and treatment responses.

ObjectivesLockdowns and outing restrictions during the COVID-19 pandemic may have altered attitudes towards hospital visits. This study aimed to investigate changes in long-distance visits outside of secondary healthcare service areas (SHSA) among cancer patients in Japan.DesignRetrospective observational study.SettingInpatient data from the Japanese Diagnosis Procedure Combination database.Primary and secondary outcome measuresWe retrospectively analysed inpatient data from January 2018 to December 2021, extracted from the Japanese Diagnosis Procedure Combination database. The study examined whether the patient’s hospital was within their residence’s SHSA and compared the admission rates before and after the pandemic.ResultsThe data of a total of 2 394 760 patients were analysed. Admission rates outside the SHSA significantly decreased after the pandemic compared with prepandemic years (26.67% and 27.58%, respectively, p<0.001). Significant reductions were observed in nearly all age groups over 30 years old, but not in younger ones. Characteristics of patients’ residences, including COVID-19 infection rates, population density and the number of regional cancer hospitals, were also influential factors. The cancer site was a significant factor, with the respiratory system showing a 3.77% decrease, particularly a 5.29% decrease in those who needed surgeries that are not highly specialised (p<0.001).ConclusionsAdmission to distant hospitals among cancer patients decreased following the COVID-19 pandemic, indicating a restraint in their behaviour of visiting distant hospitals. The appropriate allocation of specialised hospitals will serve as a measure for the next pandemic.

Imaging and measuring compression stresses secure a safe and healthy life. Compression stresses in kPa range are not easily detected by conventional mechanoresponsive materials because microscopic molecular motion of the chromophores is not induced by such weak stresses. Moreover, imaging of the stress distribution is not achieved so far. The present study shows a sponge device combining two stimuli‐responsive materials, a capsule releasing interior liquid and color‐changing polymer in responses to compression stress and chemical stimulus, respectively. The stimuli‐responsive capsule is dispersed on a melamine sponge comprised of the fibers with coating the layered polydiacetylene (PDA). The application of weak compression stresses induces collapse of the capsules, outflow of the interior liquid, and subsequent irreversible color change of PDA. The cascading response in the sponge device colorimetrically enables imaging of the distribution and measuring the strength of the compression stresses in kPa range. Furthermore, the device demonstrates imaging and measuring unknown weak compression stresses applied by the irregular‐shaped objects. A couple of clinical issues in surgical operation of intestine are studied using the stress‐imaging sponge device. The device and its design strategy can be applied to stress imaging in a variety of fields. Imaging invisible force distribution is a significant challenge in chemistry and materials science. The present work shows stimuli‐responsive sponge device for imaging and measuring weak compression stresses in kPa range and mm scale. The device visualizes and quantifies the local compression stress and its distribution applied by irregularly shaped objects, such as plastic ornaments and surgical devices.