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1.
Cell ; 180(2): 248-262.e21, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31978344

RESUMO

The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Our single-cell transcriptomic data of human and mouse spermatogenesis provide evidence that this widespread transcription maintains DNA sequence integrity in the male germline by correcting DNA damage through a mechanism we term transcriptional scanning. We find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary timescales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning shapes germline mutation signatures and modulates mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for faster evolution in a specific subset.


Assuntos
Expressão Gênica/genética , Mutação em Linhagem Germinativa/genética , Espermatogênese/genética , Adulto , Animais , Sequência de Bases/genética , Perfilação da Expressão Gênica/métodos , Células Germinativas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Taxa de Mutação , Testículo/metabolismo , Transcrição Gênica/genética , Transcriptoma/genética
2.
Nature ; 596(7871): 211-220, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34381231

RESUMO

Deciphering the principles and mechanisms by which gene activity orchestrates complex cellular arrangements in multicellular organisms has far-reaching implications for research in the life sciences. Recent technological advances in next-generation sequencing- and imaging-based approaches have established the power of spatial transcriptomics to measure expression levels of all or most genes systematically throughout tissue space, and have been adopted to generate biological insights in neuroscience, development and plant biology as well as to investigate a range of disease contexts, including cancer. Similar to datasets made possible by genomic sequencing and population health surveys, the large-scale atlases generated by this technology lend themselves to exploratory data analysis for hypothesis generation. Here we review spatial transcriptomic technologies and describe the repertoire of operations available for paths of analysis of the resulting data. Spatial transcriptomics can also be deployed for hypothesis testing using experimental designs that compare time points or conditions-including genetic or environmental perturbations. Finally, spatial transcriptomic data are naturally amenable to integration with other data modalities, providing an expandable framework for insight into tissue organization.


Assuntos
Perfilação da Expressão Gênica/métodos , Especificidade de Órgãos/genética , Transcriptoma , Animais , Análise de Dados , Doença/genética , Humanos , Transcrição Gênica/genética
3.
Genome Res ; 31(10): 1719-1727, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34599005

RESUMO

Phenotypic heterogeneity within malignant cells of a tumor is emerging as a key property of tumorigenesis. Recent work using single-cell transcriptomics has led to the identification of distinct cancer cell states across a range of cancer types, but their functional relevance and the advantage that they provide to the tumor as a system remain elusive. We present here a definition of cancer cell states in terms of coherently and differentially expressed gene modules and review the origins, dynamics, and impact of states on the tumor system as a whole. The spectrum of cell states taken on by a malignant population may depend on cellular lineage, epigenetic history, genetic mutations, or environmental cues, which has implications for the relative stability or plasticity of individual states. Finally, evidence has emerged that malignant cells in different states may cooperate or compete within a tumor niche, thereby providing an evolutionary advantage to the tumor through increased immune evasion, drug resistance, or invasiveness. Uncovering the mechanisms that govern the origin and dynamics of cancer cell states in tumorigenesis may shed light on how heterogeneity contributes to tumor fitness and highlight vulnerabilities that can be exploited for therapy.


Assuntos
Neoplasias , Evolução Biológica , Carcinogênese , Transformação Celular Neoplásica , Humanos , Mutação , Neoplasias/patologia
4.
bioRxiv ; 2023 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-37786690

RESUMO

Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in over 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations on desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma tumor cells. In further support of a microenvironmental origin, we find that loss-of-function knockdowns of the desmosome in keratinocytes yield markedly increased proliferation of adjacent melanocytes in keratinocyte/melanocyte co-cultures. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanocytes for neoplastic transformation.

5.
Nat Genet ; 54(8): 1192-1201, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35931863

RESUMO

Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Using mouse models, we further found that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance and metastasis.


Assuntos
Neoplasias , Microambiente Tumoral , Animais , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica , Interferons , Camundongos , Neoplasias/patologia , Microambiente Tumoral/genética
7.
Nat Biotechnol ; 38(3): 333-342, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932730

RESUMO

Single-cell RNA sequencing (scRNA-seq) enables the systematic identification of cell populations in a tissue, but characterizing their spatial organization remains challenging. We combine a microarray-based spatial transcriptomics method that reveals spatial patterns of gene expression using an array of spots, each capturing the transcriptomes of multiple adjacent cells, with scRNA-Seq generated from the same sample. To annotate the precise cellular composition of distinct tissue regions, we introduce a method for multimodal intersection analysis. Applying multimodal intersection analysis to primary pancreatic tumors, we find that subpopulations of ductal cells, macrophages, dendritic cells and cancer cells have spatially restricted enrichments, as well as distinct coenrichments with other cell types. Furthermore, we identify colocalization of inflammatory fibroblasts and cancer cells expressing a stress-response gene module. Our approach for mapping the architecture of scRNA-seq-defined subpopulations can be applied to reveal the interactions inherent to complex tissues.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Pancreáticas/genética , Análise de Célula Única/métodos , Carcinoma Ductal Pancreático/cirurgia , Células Dendríticas/química , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Macrófagos/química , Análise de Sequência com Séries de Oligonucleotídeos , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Análise de Sequência de RNA , Análise Espaço-Temporal
8.
Trends Cancer ; 5(11): 655-656, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31735281

RESUMO

While intratumoral heterogeneity has been extensively studied in terms of genetic alterations and phenotypic properties such as drug resistance, only recently has single-cell RNA-seq begun to expose the remarkable transcriptional diversity within tumors. A recent study of glioblastoma by Neftel et al. supports the emerging notion of cancer cell states and demonstrates their plasticity.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Mutação
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