RESUMO
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Compartimento Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Inflamação/patologia , Monócitos/patologia , Células Mieloides/patologia , Neutrófilos/patologia , Células Estromais/metabolismo , Linfócitos T/metabolismo , Transcrição GênicaRESUMO
The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans at single-cell resolution: RAISIN RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq for label-free enrichment of rare cell types by droplet-based profiling. The 1,187,535 nuclei in our mouse atlas include 5,068 neurons from the ileum and colon, revealing extraordinary neuron diversity. We highlight circadian expression changes in enteric neurons, show that disease-related genes are dysregulated with aging, and identify differences between the ileum and proximal/distal colon. In humans, we profile 436,202 nuclei, recovering 1,445 neurons, and identify conserved and species-specific transcriptional programs and putative neuro-epithelial, neuro-stromal, and neuro-immune interactions. The human ENS expresses risk genes for neuropathic, inflammatory, and extra-intestinal diseases, suggesting neuronal contributions to disease.
Assuntos
Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Neurônios/metabolismo , Corpos de Nissl/metabolismo , RNA Mensageiro/metabolismo , Análise de Célula Única/métodos , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Relógios Circadianos/genética , Colo/citologia , Colo/metabolismo , Retículo Endoplasmático Rugoso/genética , Retículo Endoplasmático Rugoso/metabolismo , Retículo Endoplasmático Rugoso/ultraestrutura , Células Epiteliais/metabolismo , Feminino , Predisposição Genética para Doença/genética , Humanos , Íleo/citologia , Íleo/metabolismo , Inflamação/genética , Inflamação/metabolismo , Enteropatias/genética , Enteropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Corpos de Nissl/genética , Corpos de Nissl/ultraestrutura , RNA Mensageiro/genética , RNA-Seq , Ribossomos/metabolismo , Ribossomos/ultraestrutura , Células Estromais/metabolismoRESUMO
Attempts to identify physiological correlates of listening effort have mainly focused on peripheral measures (e.g. pupillometry) and auditory-evoked/event-related potentials. Although nonauditory studies have suggested that sustained time-frequency electroencephalographic (EEG) features in the θ-band (4-7 Hz) are correlated with domain-general mental effort, little work has characterized such features during effortful listening. Here, high-density EEG data was collected while listeners performed a sentence-recognition task in noise, the signal-to-noise ratio (SNR) of which varied across blocks. Frontal midline θ (Fmθ), largely driven by sources localized in or near the medial frontal cortex, showed greater power with decreasing SNR and was positively correlated with self-reports of effort. Increased Fmθ was present before speech onset and during speech presentation. Fmθ power also differed across SNRs when including only trials in which all words were recognized, suggesting that the effects were unrelated to performance differences. Results suggest that frontal cortical networks play a larger role in listening as acoustic signals are increasingly masked. Further, sustained time-frequency EEG features may usefully supplement previously used peripheral and event-related potential measures in psychophysiological investigations of effortful listening.