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1.
PLoS Comput Biol ; 20(6): e1011361, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38875302

RESUMO

Tumor microenvironments (TMEs) contain vast amounts of information on patient's cancer through their cellular composition and the spatial distribution of tumor cells and immune cell populations. Exploring variations in TMEs between patient groups, as well as determining the extent to which this information can predict outcomes such as patient survival or treatment success with emerging immunotherapies, is of great interest. Moreover, in the face of a large number of cell interactions to consider, we often wish to identify specific interactions that are useful in making such predictions. We present an approach to achieve these goals based on summarizing spatial relationships in the TME using spatial K functions, and then applying functional data analysis and random forest models to both predict outcomes of interest and identify important spatial relationships. This approach is shown to be effective in simulation experiments at both identifying important spatial interactions while also controlling the false discovery rate. We further used the proposed approach to interrogate two real data sets of Multiplexed Ion Beam Images of TMEs in triple negative breast cancer and lung cancer patients. The methods proposed are publicly available in a companion R package funkycells.


Assuntos
Comunicação Celular , Microambiente Tumoral , Microambiente Tumoral/fisiologia , Humanos , Comunicação Celular/fisiologia , Biologia Computacional/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Algoritmos , Simulação por Computador , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Modelos Biológicos , Feminino , Algoritmo Florestas Aleatórias
2.
Development ; 148(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34121118

RESUMO

Development of a branching tree in the embryonic lung is crucial for the formation of a fully mature functional lung at birth. Sox9+ cells present at the tip of the primary embryonic lung endoderm are multipotent cells responsible for branch formation and elongation. We performed a genetic screen in murine primary cells and identified aurora kinase b (Aurkb) as an essential regulator of Sox9+ cells ex vivo. In vivo conditional knockout studies confirmed that Aurkb was required for lung development but was not necessary for postnatal growth and the repair of the adult lung after injury. Deletion of Aurkb in embryonic Sox9+ cells led to the formation of a stunted lung that retained the expression of Sox2 in the proximal airways, as well as Sox9 in the distal tips. Although we found no change in cell polarity, we showed that loss of Aurkb or chemical inhibition of Aurkb caused Sox9+ cells to arrest at G2/M, likely responsible for the lack of branch bifurcation. This work demonstrates the power of genetic screens in identifying novel regulators of Sox9+ progenitor cells and lung branching morphogenesis.


Assuntos
Aurora Quinase B/genética , Aurora Quinase B/metabolismo , Células-Tronco Embrionárias/metabolismo , Endoderma/metabolismo , Pulmão/embriologia , Fatores de Transcrição SOX9/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Knockout , Organogênese , Fatores de Transcrição SOX9/genética
3.
J Cell Sci ; 131(5)2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29420299

RESUMO

ARHGAP19 is a hematopoietic-specific Rho GTPase-activating protein (RhoGAP) that acts through the RhoA/ROCK pathway to critically regulate cell elongation and cytokinesis during lymphocyte mitosis. We report here that, during mitosis progression, ARHGAP19 is sequentially phosphorylated by the RhoA-activated kinases ROCK1 and ROCK2 (hereafter ROCK) on serine residue 422, and by CDK1 on threonine residues 404 and 476. The phosphorylation of ARHGAP19 by ROCK occurs before mitosis onset and generates a binding site for 14-3-3 family proteins. ARHGAP19 is then phosphorylated by CDK1 in prometaphase. The docking of 14-3-3 proteins to phosphorylated S422 protects ARHGAP19 from dephosphorylation of the threonine sites and prevents ARHGAP19 from relocating to the plasma membrane during prophase and metaphase, thus allowing RhoA to become activated. Disruption of these phosphorylation sites results in premature localization of ARHGAP19 at the cell membrane and in its enrichment to the equatorial cortex in anaphase leading to cytokinesis failure and cell multinucleation.


Assuntos
Citocinese/genética , Proteínas Ativadoras de GTPase/genética , Mitose/genética , Proteína rhoA de Ligação ao GTP/genética , Proteínas 14-3-3/genética , Proteína Quinase CDC2/genética , Humanos , Células Jurkat , Fosforilação/genética , Prometáfase/genética , Serina/genética , Quinases Associadas a rho/genética
4.
Genome Biol ; 25(1): 99, 2024 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637899

RESUMO

Spatial molecular data has transformed the study of disease microenvironments, though, larger datasets pose an analytics challenge prompting the direct adoption of single-cell RNA-sequencing tools including normalization methods. Here, we demonstrate that library size is associated with tissue structure and that normalizing these effects out using commonly applied scRNA-seq normalization methods will negatively affect spatial domain identification. Spatial data should not be specifically corrected for library size prior to analysis, and algorithms designed for scRNA-seq data should be adopted with caution.


Assuntos
Perfilação da Expressão Gênica , Análise de Célula Única , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Perfilação da Expressão Gênica/métodos , Algoritmos , Biologia
5.
Cancer Cell ; 41(5): 837-852.e6, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-37086716

RESUMO

Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células T de Memória , Memória Imunológica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Pulmão , Linfócitos T CD8-Positivos
6.
Transl Lung Cancer Res ; 10(6): 2819-2829, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34295680

RESUMO

T cell memory is critical in controlling infection and plays an important role in anti-tumor responses in solid cancers. While effector memory and central memory T cells circulate and patrol non-lymphoid and lymphoid organs respectively, tissue resident memory T cells (TRM) permanently reside in tissues and provide local protective immune responses. In a number of solid tumors, tumor-specific T cell memory responses likely play an important role in keeping tumors in check, limiting cancer cell dissemination and reducing risk of relapse. In non-small cell lung cancer (NSCLC), a subset of tumor infiltrating lymphocytes (TILs) display phenotypic and functional characteristics associated with lung TRM (TRM-like TILs), including the expression of tissue-specific homing molecules and immune exhaustion markers. High infiltration of TRM-like TILs correlates with better survival outcomes for lung cancer patients, indicating that TRM-like TILs may contribute to anti-tumor responses. However, a number of TRM-like TILs do not display tumor specificity and the exact role of TRM-like TILs in mediating anti-tumor response in lung cancer is unclear. Here we review the characteristics of TRM-like TILs in lung cancer, the role these cells play in mediating anti-tumor immunity and the therapeutic implications of TRM-like TILs in the use and development of immunotherapy for lung cancer.

7.
Cancer Discov ; 10(10): 1489-1499, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32690541

RESUMO

Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27-CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGNIFICANCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.See related commentary by Krysan et al., p. 1442.This article is highlighted in the In This Issue feature, p. 1426.


Assuntos
Carcinoma de Células Escamosas/imunologia , Vigilância Imunológica/imunologia , Neoplasias Pulmonares/imunologia , Humanos
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