Similar Datasets
Project description:Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a trans-differentiation event in this disease.
| S-EPMC6075037 | biostudies-literature
Project description:Chromatin immunoprecipitation analysis by high throughput sequencing
2018-06-22 | GSE115123 | GEO
Project description:Transcriptome analysis by high throughput sequencing
2018-06-22 | GSE115122 | GEO
Project description:POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer
| PRJNA473826 | ENA
Project description:POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer [ChIP-seq]
| PRJNA473830 | ENA
Project description:POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer [RNA-seq]
| PRJNA473832 | ENA
Project description:BackgroundSmall cell lung cancer (SCLC) is a progressive disease with a poor prognosis. Recently, a method to classify SCLC by the expression status of four transcription factors, ASCL1, NEUROD1, POU2F3, and YAP1, was proposed. Here, we investigated the potential relationships between expression of these four transcription factors and the effect of lurbinectedin.MethodsmRNA and protein expression of ASCL1, NEUROD1, POU2F3, and YAP1 were quantified in eight SCLC cell lines and analyzed for potential correlations with drug sensitivity. In addition, ASCL1, NEUROD1, POU2F3, and YAP1 expression were evaluated in 105 resected cases of high-grade neuroendocrine carcinoma of the lung, including 59 resected cases of SCLC.ResultsBased on the results of qRT-PCR and western blot analyses, the eight SCLC cell lines examined were classified into NEUROD1, POU2F3, and YAP1 subtypes, as well as five ASCL1 subtypes. There were no correlations between cell line subtype classification and drug sensitivity to cisplatin, etoposide, or lurbinectedin. Next, we compared relative mRNA expression levels of each transcription factor with drug sensitivity and found that the higher the mRNA expression level of POU2F3, the lower the IC50 of lurbinectedin. Evaluation of resected SCLC tissue revealed that the composition of subtypes defined by the relative dominance of ASCL1, NEUROD1, POU2F3, and YAP1 was as follows: 61% ASCL1, 15% NEUROD1, 14% POU2F3, 5% YAP1, and 5% all-negative.ConclusionIn our experiments, high mRNA expression of POU2F3 in SCLC cell lines correlated with the effect of lurbinectedin.
| S-EPMC9013643 | biostudies-literature
Project description:Extrapulmonary neuroendocrine carcinomas (EP-NECs) are associated with a poor clinical outcome, and limited information is available on the biology and treatment of EP-NECs. We studied EP-NECs by applying the recent novel findings from studies of pulmonary neuroendocrine carcinomas, including POU2F3, the master regulator of tuft cell variant of small cell lung carcinomas. A cohort of 190 patients with surgically resected EP-NECs or poorly differentiated carcinomas (PDCs) were established. Immunohistochemistry (IHC) for POU2F3 along with ASCL1, NEUROD1, YAP1, and conventional neuroendocrine markers was performed on tissue microarrays. Selected cases with or without POU2F3 expression were subjected to targeted gene expression profiling using nCounter PanCancer Pathway panel. POU2F3-positive tuft cell carcinomas were present in 12.6% of EP-NEC/PDCs, with variable proportions according to organ systems. POU2F3 expression was negatively correlated with the expression levels of ASCL1, NEUROD1, and conventional neuroendocrine markers (P<0.001), enabling IHC-based molecular classification into ASCL1-dominant, NEUROD1-dominant, POU2F3-dominant, YAP1-dominant, and not otherwise specified subtypes. Compared wih POU2F3-negative cases, POU2F3-positive tuft cell carcinomas showed markedly higher expression levels of PLCG2 and BCL2, which was also validated in the entire cohort by IHC. In addition to POU2F3, YAP1-positive tumors were a distinct subtype among EP-NEC/PDCs, characterized by unique T-cell inflamed microenvironment. We found rare extrapulmonary POU2F3-positive tumors arising from previously unappreciated cells of origin. Our data show novel molecular pathologic features of EP-NEC/PDCs including potential therapeutic vulnerabilities, thereby emphasizing the need for focusing on unique features of EP-NEC/PDCs.
| S-EPMC9833113 | biostudies-literature
Project description:Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system xc-, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.
| S-EPMC10760199 | biostudies-literature
Project description:Transient receptor potential channel M5 (Trpm5)-expressing cells, such as sweet, umami, and bitter taste cells in the oropharyngeal epithelium, solitary chemosensory cells in the nasal respiratory epithelium, and tuft cells in the small intestine, that express taste-related genes function as chemosensory cells. Previous studies demonstrated that Skn-1a/Pou2f3, a POU homeodomain transcription factor is expressed in these Trpm5-expressing chemosensory cells, and is necessary for their generation. Trpm5-expressing cells have recently been found in trachea, auditory tube, urethra, thymus, pancreatic duct, stomach, and large intestine. They are considered to be involved in protective responses to potential hazardous compounds as Skn-1a-dependent bitter taste cells, respiratory solitary chemosensory cells, and intestinal tuft cells are. In this study, we examined the expression and function of Skn-1a/Pou2f3 in Trpm5-expressing cells in trachea, auditory tube, urethra, thymus, pancreatic duct, stomach, and large intestine. Skn-1a/Pou2f3 is expressed in a majority of Trpm5-expressing cells in all tissues examined. In Skn-1a/Pou2f3-deficient mice, the expression of Trpm5 as well as marker genes for Trpm5-expressing cells were absent in all tested tissues. Immunohistochemical analyses demonstrated that two types of microvillous cells exist in trachea, urethra, and thymus, Trpm5-positive and Trpm5-negative cells. In Skn-1a/Pou2f3-deficient mice, a considerable proportion of Trpm5-negative and villin-positive microvillous cells remained present in these tissues. Thus, we propose that Skn-1a/Pou2f3 is the master regulator for the generation of the Trpm5-expressing microvillous cells in multiple tissues.
| S-EPMC5720759 | biostudies-literature