Ablation of p57+ Quiescent Cancer Stem Cells Suppresses Recurrence after Chemotherapy of Intestinal Tumors.

Quiescent cancer stem cells (CSC) are resistant to conventional anticancer treatments and have been shown to contribute to disease relapse after therapy in some cancer types. The identification and characterization of quiescent CSCs could facilitate the development of strategies to target this cell population and block recurrence. Here, we established a syngeneic orthotopic transplantation model in mice based on intestinal cancer organoids to profile quiescent CSCs. Single-cell transcriptomic analysis of the primary tumors formed in vivo revealed that conventional Lgr5high intestinal CSCs comprise both actively and slowly cycling subpopulations, the latter of which specifically expresses the cyclin-dependent kinase inhibitor p57. Tumorigenicity assays and lineage tracing experiments showed that the quiescent p57+ CSCs contribute in only a limited manner to steady-state tumor growth but they are chemotherapy resistant and drive posttherapeutic cancer recurrence. Ablation of p57+ CSCs suppressed intestinal tumor regrowth after chemotherapy. Together, these results shed light on the heterogeneity of intestinal CSCs and reveal p57+ CSCs as a promising therapeutic target for malignant intestinal cancer. SIGNIFICANCE: A quiescent p57+ subpopulation of intestinal CSCs is resistant to chemotherapy and can be targeted to effectively suppress the recurrence of intestinal cancer.

Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium.

Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57+ cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury. Single-cell transcriptomics analysis shows that the p57+ cells undergo a dynamic reprogramming process after injury that is characterized by fetal-like conversion and metaplasia-like transformation. Population-level analysis also detects such spatiotemporal reprogramming widely in other differentiated cell types. In intestinal adenoma, p57+ cells manifest homeostatic stem cell activity, in the context of constitutively activated spatiotemporal reprogramming. Our results highlight a pronounced plasticity of the intestinal epithelium that supports maintenance of tissue integrity in normal and neoplastic contexts.

Factors Affecting Psychological Stress in Healthcare Workers with and without Chronic Pain: A Cross-Sectional Study Using Multiple Regression Analysis.

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Factors Affecting Psychological Stress in Healthcare Workers with and without Chronic Pain: A Cross-Sectional Study Using Multiple Regression Analysis.

Background and Objectives: Pain affects psychological stress and general health in the working population. However, the factors affecting psychological job stress related to chronic pain are unclear. This study aimed to clarify the structural differences among factors affecting psychological job stress in workers with chronic pain and those without pain. Materials and Methods: A stepwise multiple regression analysis revealed the differences in structure between the psychological stress of workers with chronic pain and those with no pain. Psychological job stress by the Brief Job Stress Questionnaire was used as the dependent variable, with psychological state (depression and anxiety), specifically that characteristic of chronic pain (pain catastrophizing); information on the nature of the pain (intensity and duration); and number of years of service as independent variables. Selected independent variables were evaluated for collinearity. Results: In the model with psychological stress as a dependent variable (chronic pain: r2 = 0.57, F = 41.7, p < 0.0001; no-pain: r2 = 0.63, F = 26.3, p < 0.0001), the difference between the experiences of workers with chronic pain and those with no pain was that chronic pain was associated with depression (Beta = 0.43, p < 0.0001) and no pain with anxiety (Beta = 0.34, p < 0.0001). In the model with chronic pain-related depression as a dependent variable (r2 = 0.62, F = 41.7, p < 0.0001), job-life satisfaction (Beta = -0.18, p = 0.0017) and magnification (a dimension of pain catastrophizing; Beta = 0.16, p < 0.0001) were significant. Conclusions: The results of this study suggest that the psychological characteristics of chronic pain, such as depression and magnification, should be considered when evaluating and intervening in the job stress of workers with chronic pain.

Nuclear-cytoplasmic shuttling protein PP2AB56 contributes to mTORC1-dependent dephosphorylation of FOXK1.

Mammalian target of rapamycin complex 1 (mTORC1) kinase is a master regulator of the cellular response to nutrition-related signals such as insulin and amino acids. mTORC1 is activated on the lysosomal membrane and induces phosphorylation of a variety of downstream molecules. We previously showed that activated mTORC1 induces protein phosphatase 2A (PP2A)-mediated dephosphorylation of the transcription factor forkhead box K1 (FOXK1). The mechanism underlying the signal transduction from the cytoplasmic mTORC1 to the nuclear FOXK1 has remained unclear, however, we now show that a nuclear-cytoplasmic transport system is necessary for the mTORC1-FOXK1 signal transduction. This reaction is mediated by a shuttling protein B56, which is a regulatory subunit of PP2A and plays an essential role in the mTORC1-dependent dephosphorylation of FOXK1. These results suggest that PP2AB56 phosphatase contributes to the signaling for mTORC1-dependent transcriptional regulation.

The Autism-Related Protein CHD8 Cooperates with C/EBPß to Regulate Adipogenesis.

The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein ß (C/EBPß) and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the upregulation of C/EBPα and peroxisome-proliferator-activated receptor γ (PPARγ), two master regulators of this process, being attenuated in mutant cells. Furthermore, mice with CHD8 ablation in white preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a mode of C/EBPß regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue.