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1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR131/094/SRR13165994/SRR13165994_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/088/SRR11388788/SRR11388788_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/046/SRR11388746/SRR11388746_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/040/SRR11388740/SRR11388740_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/064/SRR11388764/SRR11388764_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/022/SRR11388722/SRR11388722_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/098/SRR11388798/SRR11388798_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/037/SRR11388737/SRR11388737_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/092/SRR11388792/SRR11388792_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR131/086/SRR13165986/SRR13165986_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/023/SRR11388723/SRR11388723_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/073/SRR11388773/SRR11388773_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/032/SRR11388732/SRR11388732_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR131/004/SRR13166004/SRR13166004_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/097/SRR11388797/SRR11388797_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/056/SRR11388756/SRR11388756_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/047/SRR11388747/SRR11388747_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/082/SRR11388782/SRR11388782_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR113/014/SRR11388714/SRR11388714_1.fastq.gzprimaryOK200GenomicsDepartment of Biomedical Engineering, University of Virginiahttps://www.ebi.ac.uk/ena/browser/view/PRJNA614003Mus musculusSmall-cell lung cancers derive from pulmonary neuroendocrine cells, which have stem-like properties to reprogram into other cell types upon lung injury. It is difficult to uncouple the plasticity of these transformed cells from heritable changes that evolve in primary tumors or select in metastases to distant organs. Approaches to single-cell profiling are also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here, we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. Using a labeled murine isolate from small-cell lung cancer initiated by neuroendocrine deletion of p53 and Rb, we profiled cell-to-cell transcriptional-regulatory heterogeneity in spheroid cultures and liver colonies seeded intravenously. Fluctuating transcripts in vitro were partly shared with other epithelial-spheroid models, and candidate heterogeneities increased considerably when cells were delivered to the liver. Colonization of immunocompromised animals drove the fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. We identified dozens of transcript heterogeneities that recur irrespective of biological context their orthologs merged observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype. We conclude that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer. Overall design: 10-cell samples from murine small-cell lung cancer spheroids and liver colonies from both immunocompromised and immuncompetent mice were captured by laser. mRNA was extracted and PCR amplified for RNA-sequencing. capture microdissectionENASmall Cell Carcinoma of the Lung, Oat Cell Carcinoma, small-cell lung cancer, poorly differentiated endocrine neoplasm, Oat Cell Lung Carcinoma, Small Cell Neuroendocrine Carcinoma of Lung, Lung Oat Cell Carcinoma, Oat Cell Carcinomas, small cell lung carcinoma, oat cell lung carcinoma, Lung Small Cell Neuroendocrine Carcinoma, lung small cell neuroendocrine carcinoma, small cell neuroendocrine carcinoma of the lung, Small Cell Neuroendocrine Carcinoma of the Lung, Oat cell carcinoma of lung (disorder), small cell carcinoma of lung, oat cell carcinoma of lung, small cell lung cancer, oat cell carcinoma (morphologic abnormality), SCLC - Small cell lung cancer, SCLC, small cell neuroendocrine carcinoma of lung, small cell carcinoma of the lung, small cell cancer of the lung, small cell carcinoma of lung (disorder), oat cell carcinoma., oat cell carcinoma of the lung, Oat cell carcinoma of lung, lung small cell carcinoma, Oat Cell Carcinoma of the Lung, Small cell lung cancer, lung oat cell carcinoma, Small Cell Carcinoma of Lung, SCLC1Small Cell Carcinoma of the Lung, Oat Cell Carcinoma, small-cell lung cancer, poorly differentiated endocrine neoplasm, Oat Cell Lung Carcinoma, Small Cell Neuroendocrine Carcinoma of Lung, Lung Oat Cell Carcinoma, Oat Cell Carcinomas, small cell lung carcinoma, oat cell lung carcinoma, Lung Small Cell Neuroendocrine Carcinoma, lung small cell neuroendocrine carcinoma, small cell neuroendocrine carcinoma of the lung, Small Cell Neuroendocrine Carcinoma of the Lung, Oat cell carcinoma of lung (disorder), small cell carcinoma of lung, oat cell carcinoma of lung, small cell lung cancer, oat cell carcinoma (morphologic abnormality), SCLC - Small cell lung cancer, SCLC, small cell neuroendocrine carcinoma of lung, small cell carcinoma of the lung, small cell cancer of the lung, small cell carcinoma of lung (disorder), oat cell carcinoma., oat cell carcinoma of the lung, Oat cell carcinoma of lung, lung small cell carcinoma, Oat Cell Carcinoma of the Lung, Small cell lung cancer, lung oat cell carcinoma, Small Cell Carcinoma of Lung, SCLC1falseFragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic MicroenvironmentsFragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments2025-09-242021-01-21PRJNA614003GSE14735810090