Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer [Single cell RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1171367 | ENA |
REPOSITORIES: ENA
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Project description:Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes. The mechanisms driving neuroendocrine–tuft tumour heterogeneity, and the origins of tuft-like cancers are unknown. Using multiple genetically-engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine–tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovers unexpected transcriptional states and lineage trajectories underlying neuroendocrine–tuft plasticity. Uniquely in basal cells, introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss, and ASCL1 suppression, cooperate to promote tuft-like tumours. Transcriptomics of 944 human SCLCs reveal a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate remarkable conservation between cancer states and normal basal cell injury response mechanisms. Together, these data suggest that the basal cell is a plausible origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine–tuft heterogeneity—offering new insights for targeting lineage plasticity.
2025-07-01 | GSE279200 | GEO
Project description:While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4Ra signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.
2022-09-14 | GSE197156 | GEO
Project description:While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4Ra signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.
2022-09-14 | GSE197162 | GEO
Project description:The goal of the study was to sequence mRNA from tuft cells (identified as CD45-;EpCAM+;IL-25+ using Flare25 reporter mice) in the epithelia of 5 different murine tissues: trachea, thymus, colon, gall baldder, small intestine. As a control, non-tuft epithelial cells (CD45-;EpCAM+;IL-25-) were also isolated. The data were used to identify differentially expressed genes across tuft cells from different tissues and to define a transcriptional tuft cell "signature" that is common to all tissues analyzed but absent in the non-tuft epithelial cells.
2018-05-05 | GSE114067 | GEO
Project description:The tuft cell–ILC2 circuit orchestrates rapid type 2 responses upon detecting microbe-derived succinate and luminal helminths. Our findings delineate key mechanistic steps, involving IP3R2 engagement and Ca2+ flux, governing IL-25 production by tuft cells triggered by succinate detection. While IL-17RB plays a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Suboptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb-deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.
2025-01-21 | GSE279898 | GEO
Project description:Lung tuft cell transcriptomics
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Project description:The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To clarify how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (Just EGFP Death Inducing) CD8+ T cells into tuft cell reporter mice (Gfi1b-GFP). Surprisingly, some tuft cells partially resist JEDI CD8+ T cell-mediated killing – unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells – despite seemingly normal antigen presentation. When targeting tuft cells, JEDI CD8+ T cells predominantly adopt a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. Importantly, JEDI CD8+ T cells neither clear nor prevent MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen (e.g., GFP).
2023-12-08 | GSE249744 | GEO
Project description:The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To clarify how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (Just EGFP Death Inducing) CD8+ T cells into tuft cell reporter mice (Gfi1b-GFP). Surprisingly, some tuft cells partially resist JEDI CD8+ T cell-mediated killing – unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells – despite seemingly normal antigen presentation. When targeting tuft cells, JEDI CD8+ T cells predominantly adopt a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. Importantly, JEDI CD8+ T cells neither clear nor prevent MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen (e.g., GFP).
2023-12-08 | GSE242118 | GEO
Project description:The goal of the study was to sequence mRNA from tuft cells (identified as CD45-;EpCAM+;IL-25+ using Flare25 reporter mice) in the epithelia of thymus and small intestine. As a control, non-tuft epithelial cells (CD45-;EpCAM+;IL-25-) were also isolated. The data were used to compare tuft cell markers between the small intestine and thymus.
2018-05-19 | GSE114668 | GEO
Project description:We previously identified Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal tumors. In this study, we have identified IL17RB as a cell surface marker distinctively expressed by Dclk1+ tuft-like tumor cells in mouse intestinal tumors. Using this tuft cell marker, we compared and analyzed the transcriptome of Lgr5-tuft marker-, Lgr5+tuft marker-, Lgr5-tuft marker+, and Lgr5+tuft marker+ tumor cells. These analyses revealed that tuft-like tumor cells in the intestinal tumors comprise two distinct subsets: highly differentiated tuft-like tumor cells (Lgr5-tuft marker+ cells) and tuft-like tumor cells with TCS potential (Lgr5+tuft marker+ cells).
2021-02-19 | GSE118853 | GEO